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PHARMACOGENOMICS
Challenges and Opportunities in
Therapeutic Implementation
SECOND EDITION
Edited by
Y. W. Francis Lam
Stuart A. Scott
Academic Press is an imprint of Elsevier
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This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as
may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any
information, methods, compounds, or experiments described herein. In using such information or methods they should
be mindful of their own safety and the safety of others, including parties for whom they have a professional
responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any
injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or
operation of any methods, products, instructions, or ideas contained in the material herein.
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Dr. Lam dedicates this book to Jennifer, Jessica, and Derek;
Aunt Chee-Ming and Uncle Po-Hon; Mom and Dad.
Dr. Scott dedicates this book to Gillian, Camille, and Harvey.

List of Contributors
Rector Arya South Texas Diabetes and Obesity Christopher P. Jenkinson South Texas Diabetes
Institute, University of Texas Rio Grande Valley and Obesity Institute, University of Texas Rio
School of Medicine, Edinburg, TX, United States Grande Valley School of Medicine, Edinburg, TX,
Mariana R. Botton Department of Genetics and United States
Genomic Sciences, Icahn School of Medicine at Y. W. Francis Lam Department of Pharmacology,
Mount Sinai, New York, NY, United States University of Texas Health Science Center at San
Karla Claudio Campos Department of Pharmaco Antonio, San Antonio, TX, United States; College
therapy and Translational Research, University of Pharmacy, University of Texas at Austin, Austin,
of Florida College of Pharmacy, Gainesville, FL, TX, United States
United States Edmund Jon Deoon Lee Pharmacogenetics
Kelly E. Caudle Pharmaceutical Sciences Department, Laboratory, Department of Pharmacology, Yong
St. Jude Children’s Research Hospital, Memphis, TN, Loo Lin School of Medicine, National University of
United States Singapore, Singapore
Larisa H. Cavallari Department of Pharmaco Michael Limenta Health Products Regulation
therapy and Translational Research and Center Group, Health Sciences Authority, Singapore
for Pharmacogenomics, University of Florida, Surulivelrajan Mallayasamy Post-Doctoral Research
Gainesville, FL, United States Associate, Department of Pharmaco therapy,
Katarzyna Drozda Office of Clinical Pharmacology, University of North Texas System College of
Food and Drug Administration, Silver Spring, MD, Pharmacy, Fort Worth, TX, United States; Department
United States of Pharmacy Practice, MCOPS, Manipal University,
Manipal, India
Jorge Duconge Department of Pharmaceutical
Sciences, School of Pharmacy, University of Puerto Elsa Haniffah Mejia Mohamed Pharmacogenomics
Rico Medical Sciences Campus, San Juan, PR, Laboratory, Department of Pharmacology,
United States University Malaya, Kuala Lumpur, Malaysia;
Pharmacogenetics Laboratory, Department of
Ravindranath Duggirala South Texas Diabetes
Pharmacology, National University of Singapore,
and Obesity Institute, University of Texas Rio
Singapore
Grande Valley School of Medicine, Edinburg, TX,
United States Kathryn M. Momary Department of Pharmacy
Practice, Mercer University, College of Pharmacy,
Henry M. Dunnenberger Pharmacogenomics, Center
Atlanta, GA, United States
for Molecular Medicine, NorthShore University
Health System, Evanston, IL, United States Aniwaa Owusu Obeng The Charles Bronfman
Institute for Personalized Medicine, Icahn School
Roseann S. Gammal Department of Pharmacy
of Medicine at Mount Sinai, Department of
Practice, MCPHS University, Boston, MA, United
Pharmacy, The Mount Sinai Hospital, New York,
States; Pharmaceutical Sciences Department, St.
NY, United States
Jude Children’s Research Hospital, Memphis, TN,
United States
xiii
xiv List of Contributors
Scott R. Penzak Department of Pharmacotherapy, Toshiyuki Someya Department of Psychiatry,

University of North Texas System College of Niigata University Graduate School of Medical and
Pharmacy, Fort Worth, TX, United States Dental Sciences, Niigata, Japan
Matthias Samwald Center for Medical Statistics, Jesse J. Swen Department of Clinical Pharmacy
Informatics, and Intelligent Systems, Medical and Toxicology, Leiden University Medical Center,
University of Vienna, Vienna, Austria Leiden, The Netherlands
Erick R. Scott Department of Genetics and Genomic Wei Chuen Tan-Koi Health Products Regulation
Sciences, Icahn School of Medicine at Mount Sinai, Group, Health Sciences Authority, Singapore
New York, NY, United States; Clinical Data Science, Alexander Vandell Daiichi Sankyo Pharma
Sema4, Stamford, CT, United States Development, Basking Ridge, NJ, United States
Stuart A. Scott Department of Genetics and Richard L. Wallsten Clinical Data Science, Sema4,
Genomic Sciences, Icahn School of Medicine at Stamford, CT, United States
Mount Sinai, New York, NY, United States; Sema4,
Ophelia Yin Daiichi Sankyo Pharma Development,
Stamford, CT, United States
Basking Ridge, NJ, United States
Preface
Pharmacogenomics and pharmacogenetics book. In addition, we have included two chap-

are overlapping sciences, and, although the two ters that discuss the complexity of ethnicity in
terminologies have been used interchangeably pharmacogenomics studies and global drug
in the literature, pharmacogenomics reflects a development, and several chapters that discuss
progressive transition that has taken place over practical aspects of pharmacogenomics testing.
the years within the broad scope of personalized The book chapters are organized into three sec-
medicine. As a discipline, pharmacogenomics is tions. The first section (Chapters 1 to 4) provides
envisioned as a major societal benefit from all an introductory chapter on pharmacogenomics,
the scientific and technical advances related to one on industry perspective and insights for
the Human Genome Project. To date, much work the role of pharmacogenomics in drug develop-
remains to address the challenges with translat- ment, another on global academic and govern-
ing pharmacogenomics into clinical practice mental efforts to advance and apply the relevant
and drug development to achieve the ultimate genomic knowledge, and an overview chapter
goal envisioned many years ago. Nevertheless, on the challenges of moving the discipline into
examples of clinical applications of pharma- real-world settings over the last decade. The sec-
cogenomics knowledge have emerged at several ond section (Chapters 5 to 9) primarily focuses
major academic medical centers. on clinical areas in which the evidence supports
This book differs from available pharmacoge- direct pharmacogenetic applications to patient
nomics books in several aspects. It neither con- care. When appropriate, unsuccessful applica-
tains significant materials on molecular genetics tions are used to illustrate the challenges for the
nor lists all the theoretical pharmacogenomics discipline. The third section (Chapters 10 to 15)
applications organized by therapeutic special- is unique and covers diverse topics including
ties. Rather, the focus of the book is to provide looking to the future for pharmacogenomics
a timely discussion and viewpoints on a broad data technologies, pharmacogenomics issues in
range of topics; from the academic, regulatory, different ethnic populations, as well as different
pharmaceutical, clinical, socioethical, and eco- models and economic evaluations of pharma-
nomic perspectives that are relevant to the com- cogenomics testing. The final chapter provides a
plex processes in translating pharmacogenomics resource as to how this textbook can be useful for
findings into therapeutic applications. teaching pharmacogenomics to students in vari-
As with the first edition, our goal has been ous healthcare disciplines and graduate-level
to provide information that is not readily avail- students in health and pharmaceutical sciences,
able in other books covering the same topic. as well as how pharmacogenomics information
Although the processes and implementation can be integrated into clinical practice.
barriers are presented in depth in one chapter, Because the book details viewpoints on the
perspectives on challenges and limitations, as challenges of translating pharmacogenomics,
well as examples of successful direct therapeu- we intentionally did not “limit” our contribu-
tic applications, are presented throughout the tors with “organized content” for each chapter.
xv
xvi Preface
In essence, each chapter simply follows a gen- specific materials covered in the book would be
eral approach of including an overview of the useful resources for teaching graduate students
potentials or opportunities within the context in academic disciplines such as pharmacology,
of the respective chapter, but the emphasis is on neuroscience, structural and cellular biology,
discussion of barriers with perspectives on how and molecular medicine. It is our sincere hope
to move pharmacogenomics forward. Realizing that after completing the textbook, the readers
that overlap is inevitable in a book with multiple not only have a critical awareness of the value of
authors, we took measures to minimize unnec- pharmacogenomic implementation with actual
essary duplicated materials, and cross-reference versus potential applications, but also a broad
chapters whenever appropriate. knowledge of the pertinent issues and chal-
This book is intended not only as a reference lenges for pharmacogenomics before advances
book for scientists in academia and the pharma- in scientific findings can be broadly and practi-
ceutical industry involved in pharmacogenomics cally applied to patient care.
research, but also for healthcare clinicians work-
ing or interested in the field. In addition, this text Y. W. Francis Lam
is useful as a textbook for teaching clinicians and Stuart A. Scott
students in different healthcare disciplines, and
C H A P T E R
1
Principles of Pharmacogenomics:
Pharmacokinetic, Pharmacodynamic,
and Clinical Implications
Y. W. Francis Lam1,2
1Department of Pharmacology, University of Texas Health Science Center at San Antonio,
San Antonio, TX, United States; 2College of Pharmacy, University of Texas at Austin,
Austin, TX, United States
O U T L I N E
Objectives2 Polymorphisms in Drug-Transporter Genes 21

The ABC-Efflux Transporters 21
Introduction2
ABCB121
Polymorphisms in Cytochrome P450 Enzymes 3 ABCC1 and ABCC2 23
CYP2D64 ABCG223
CYP2C199 The SLC-Uptake Transporters 24
CYP2C911 Organic Anion Transporting Polypeptides 24
CYP2C813 OAT1B124
CYP3A4/5/713 OATP2B126
CYP4F215 OATP1B326
CYP2B615 Organic Cation Transporters 26
CYP2A617 Organic Anion Transporters 27
CYP1A217
Polymorphisms in Drug-Target Genes 27
Polymorphisms in Non-CYP450 Drug- Drug Target Receptor Genes in Oncology 28
Metabolizing Enzymes 18 Drug Target Receptor Genes in Cardiology 30
UDP-Glucuronosyl Transferase 18 Drug Target Genes in Psychiatry 32
Thiopurine-S-methyltransferase19 Drug Target Genes in Pain Management 32
Dihydropyrimidine Dehydrogenase (DYPD) 19 Signal Transduction Proteins 33
N-acetyltransferase20 Enzyme Genes 34
Glutathione-S-transferase20 Ion Channel Genotype 36
Pharmacogenomics, Second Edition

https://doi.org/10.1016/B978-0-12-812626-4.00001-2 1 © 2019 Elsevier Inc. All rights reserved.
2 1. PRINCIPLES OF PHARMACOGENOMICS: PHARMACOKINETIC, PHARMACODYNAMIC, AND CLINICAL IMPLICATIONS
Conclusion37 References37
Questions for Discussion 37
OBJECTIVES The human genome comprises approxi-

mately 20,000 protein-coding genes. By far the
1. Describe how a single-nucleotide polymor- most common variation is the single-nucleotide
phism (SNP) can affect protein function or polymorphism (SNP), which is defined as single-
expression, and consequently, influence drug base differences that exist between individuals.
response. Over 22 million SNPs have been reported in the
2. Explain how genetic polymorphisms for human genome [1]. SNPs that result in amino
drug metabolism or drug-transporter pro- acid substitution are termed nonsynonymous.
teins may influence drug pharmacokinetics. Nonsynonymous SNPs occurring in coding
3. Contrast phenotypic responses to genetic regions of the gene (e.g., exons) can impact pro-
variation for drug metabolism versus drug- tein activity and have significant consequences
target proteins. on responses to medications that depend on the
4. Describe novel drug developed based on an protein for metabolism, transport, or eliciting
understanding of genes involved in disease cellular effects. Synonymous polymorphisms do
pathophysiology. not result in amino acid substitution; however,
5. Explain how genetic polymorphisms at the those occurring in a gene regulatory region (e.g.,
drug-target site may influence drug pharma- promoter region, intron) may alter gene expres-
codynamics. sion and the amount of protein that is produced.
Two or more SNPs are often inherited together
more frequently than would be expected based
INTRODUCTION on chance alone. This is referred to as linkage
disequilibrium (LD). A haplotype refers to a set
Significant interpatient variability in drug of SNPs that are in LD. Other types of variation
response is largely attributed to innate differences that can affect gene expression or protein con-
among individuals in their capacity to process formation include insertion–deletion polymor-
and respond to medications. Pharmacogenomics phisms (indels), short tandem repeats, and copy
involves incorporating information about a per- number variants (CNVs). A CNV represents a
son’s genotype into drug therapy decisions, DNA segment (≥1 kb) with a variable number of
with the goal of providing the most effective and copies of that segment, because of duplications,
safest therapy for that individual. Over the last deletions, or rearrangement, and constitutes a
decade, there have been significant advances in major source of interindividual variation in the
our understanding of the contribution of genetic human genome. A unique reference SNP iden-
differences in pharmacokinetics and pharmaco- tifier (rs number) is assigned for each genetic
dynamics toward interindividual variability in variant, and exists as an SNP data repository, the
drug response. Not only may pharmacogenom- National Center for Biotechnology Information
ics lead to improved use of existing therapies, (NCBI) Single-Nucleotide Polymorphism
but it may also lead to novel drugs developed Database (dbSNP).
based on an improved understanding of genetic Polymorphisms commonly occur for genes
control of cellular functions. encoding drug metabolism, drug transporter,
Polymorphisms in Cytochrome P450 Enzymes 3
Despite the scientific advances made, person-
alized medicine envisioned many years ago has in
many cases yet to become a reality. Exceptions to
this largely exists in oncology and more recently
in cardiology, in which genotyping to determine
clopidogrel effectiveness is starting to become
routine at some large academic medical centers
[3,4]. Examples of genotype-guided therapies
are beginning to emerge in other therapeutic
areas, which are discussed in detail through-
out this book. However, significant challenges
still exist in ethical, socioeconomic, regulatory,
FIGURE 1.1 Location of genetic variations affecting drug legislative, drug development, and educational
response. Those occurring in genes for drug metabolism or issues that need to be addressed and resolved
transport can affect drug pharmacokinetics, whereas SNPs before personalized medicine can be practically
in genes encoding for drug-target proteins can impact drug and satisfactorily implemented in clinical prac-
pharmacodynamics.
tice on a broader scale. The goal of this chapter
is to review the pharmacokinetic and pharmaco-
and drug-target proteins (Fig. 1.1). Drug metab- dynamics basis of individualized therapy, and
olism and transporter genotypes can affect briefly discuss the challenges of implementing
drug availability at the target site, whereas pharmacogenomics in clinical practice. Further
drug-target genotype can affect a patient’s sen- indepth discussion of specific therapeutic areas
sitivity to a drug. In many instances, genes for and/or disease states, as well as ethical, socio-
proteins involved in drug disposition, together economic, regulatory, legislative, drug develop-
with genes for proteins at the drug-target site, ment, technological, and educational issues will
jointly influence drug response. In addition, be the focus of subsequent chapters.
genetic polymorphisms in absorption, distribu-
tion, metabolism, and excretion (ADME) and
target genes also contribute to ethnic heteroge- POLYMORPHISMS IN
neity in drug response [2]. Research advances CYTOCHROME P450 ENZYMES
have resulted in continued identification of
association between genetic polymorphisms The cytochrome P450 (CYP) superfamily of
and response, with recent focus on genome- isoenzymes represents the most important and
wide association studies (GWAS) in populations studied metabolic enzymes that exhibit clini-
worldwide. cally relevant genetic polymorphisms. Within
The terms pharmacogenetics and pharma- this superfamily of isoenzymes, 57 different CYP
cogenomics are often used interchangeably. genes and 58 pseudogenes have been identified,
Because drug responses are mostly determined and, based on the similarity in their amino acid
by multiple, rather than single, proteins, recent sequences, are grouped into 18 families and 44
trends of investigations on determinants of drug subfamilies with increasing extent of sequence
response have shifted from pharmacogenetics similarity. Of these genes and pseudogenes, 42 are
to pharmacogenomics. However, for simplicity, involved in the metabolism of exogenous xeno-
this chapter treats pharmacogenetics and phar- biotics and endogenous substances, such as ste-
macogenomics as synonymous. roids and prostaglandins, and 15 are known to be
involved in the metabolism of drugs in humans isoenzyme to the overall metabolism of the drug.
[5]. Information regarding CYP allele nomencla- For the majority of the drugs, PMs would exhibit
ture and specific genetic variations defining dif- a higher risk of adverse drug reactions (ADRs),
ferent metabolic phenotypes had been available whereas UMs would experience lower efficacy
at the Karolinska Institute website: www.cypal- when administered standard-dosage regimen
leles.ki.se, for more than a decade, and recently of a drug that is mostly dependent on the poly-
moved to the new Pharmacogene Variation morphic enzyme for elimination. In the case of
(PharmVar) Consortium, which serves as a new a prodrug, the UMs exhibit higher incidence of
hub for pharmacogene nomenclature [6]. ADRs, and the PMs experience lower efficacy,
The genes encoding CYPs are highly poly- reflecting a difference in the extent of therapeu-
morphic, with SNPs in the CYP gene locus tically active metabolite formed between the
accounting for most of the variations in CYP two metabolic genotypes.
activity, resulting in functional genetic poly- Among the different CYP gene polymor-
morphism for several isoenzymes, including phisms, those affecting CYP2D6, CYP2C19, and
CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2C9 are currently the most relevant with
and CYP3A4/5. Additional types of CYP poly- also the most abundant data, as well as repre-
morphisms cause gene deletions, deleterious senting most of the revised regulatory labeling
mutations resulting in premature stop codon information. Their potential role in translating
or splicing defects, amino acid changes, gene the expanding pharmacogenomic knowledge
duplications, and CNV. Different alleles or into dose requirements and therapeutic deci-
functional variants of these polymorphisms for sions will be discussed first. An overview of
individual drug metabolizing genes are defined the other major CYP isoenzymes will also be
with a “star” (*) designation. A combination of presented.
two *alleles, for example, CYP2D6*1/*1, is used
to classify individuals into several genetically
CYP2D6
defined metabolic phenotypes with different
expressions of enzyme activity. In general, the CYP2D6 is the only drug-metabolizing CYP
poor metabolizers (PMs) inherit two defective enzyme that is not inducible, and the significant
or deleted alleles and exhibit abolished-enzyme interindividual differences in enzyme activity are
activity; the intermediate metabolizers (IMs) largely attributed to genetic variations. CYP2D6
carry either one functional and one defective is located on chromosome 22 and consists of
allele, or two partially defective alleles, and, in 4382 nucleotides. The CYP2D6 gene, which
both cases, have reduced activity of the enzyme. codes for the CYP2D6 enzyme, is composed of
The normal metabolizers are typically known 497 amino acids. In addition, the CYP2D6 gene
as the extensive metabolizers (EMs) with two polymorphisms are also the best characterized
functional alleles and normal enzyme activity; among all of the CYP variants, with at least 100
and the ultrarapid metabolizers (UMs) carry a alleles identified. Nevertheless, Sistonen et al.
duplicated or amplified gene variant, resulting [7] demonstrated that, even with the extensive
in two or multiple copies of the functional allele number of alleles, determining 20 different hap-
and very high enzyme activity. lotypes by genotyping 12 SNPs could predict the
In general, the clinical consequences of genet- real phenotype with 90%–95% accuracy.
ically altered-enzyme activity would depend on Among the multiple CYP2D6 alleles,
whether the pharmacological activity resides CYP2D6*1, CYP2D6*2, CYP2D6*33, and
with the parent compound or the metabolite, CYP2D6*35 are active alleles with nor-
and the relative contribution of the polymorphic mal enzyme activity, whereas the two most
important null variants are CYP2D6*4 can also occur, resulting in different levels of
(c.1846G>A, rs3892097) and CYP2D6*5 (gene gene expression and phenotypes of metabolic
deletion), resulting in an inactive enzyme and importance (Table 1.1). A CYP activity score
absence of enzyme, respectively. Significant has also been recommended for use in classify-
reduction in enzyme activity is commonly asso- ing the different 2D6 phenotypic groups [13].
ciated with CYP2D6*10 (c.100C>T, rs1065852), More recently, a software tool (originally named
CYP2D6*17 (c.1023C>T, rs28371706, c.2850C>T, “Constellation” and subsequently renamed as
rs16947), and CYP2D6*41 (c.2988G>A, “Astrolabe”) capable of allowing rapid, auto-
rs28371725), and phenotypically expressed as IM. mated phenotype assignment has been made
In addition, to these reduced function alleles, the available for academic research at no cost [14].
IM phenotype has also been associated with the Significant interethnic variations in CYP2D6
CYP2D6*9, *29, and *36 variants [5]. Additional allele and phenotype distributions have also
loss-of-function alleles include CYP2D6*3, *6–*8, been well documented. The normal func-
*11–*16, *19–*21, *38, *40, and *42. CYP2D6 is tion CYP2D6*2 has been reported in approxi-
also the first CYP isoenzyme for which CNVs mately 25% of Caucasians, 31% of Africans, and
were reported [8]. Individuals carrying up to 13 10%–12% of East Asians [15]. CYP2D6*4 and
functional copies of the CYP2D6*2 allele [9] have CYP2D6*5 (allelic frequency of about 20%–25%
been reported to exhibit variation in response to and 4%–6%, respectively) are predominantly
different drugs [10,11]. After these initial reports, found in Caucasian PMs, whereas the predomi-
gene duplication has also been documented for nant variants in people of Asian and African
the CYP2D6*1, *4, *6, *10, *17, *29, *35, *41, *43, heritage are CYP2D6*10 (allelic frequency of
and *45 variants [12]. Therefore, although UMs about 50%) and CYP2D6*17 (allelic frequency of
can result from duplication or multiduplica- about 20%–34%), respectively, both resulting in
tion of the active CYP2D6 gene, duplication of the IM phenotype. Therefore, even though the
partially functional and nonfunctional genes classic PM phenotypic frequencies determined
TABLE 1.1 Functional CYP2D6 Polymorphisms, Expected Enzyme Activity, and Predicted Metabolic Phenotypes for
Selected Common Variants
Allelic Variants and Polymorphism Functional Effect on Enzyme Activity Predicted Metabolic Phenotypes
Active: Normal activity Extensive metabolizers:

*1, *2, *2A, *33, *35 • Homozygous carriers of two active
alleles
Partially active: Reduced activity • Heterozygous carriers of an active and
*9, *10 (P34S), *17 (T107I, R296C), a partially active allele
*29, *36, *41 (splicing defect) Intermediate metabolizers:
Inactive: Loss-of-function • Heterozygous carriers of an active and
*3 (frame shift) *4 (splicing defect), *5 a loss-of-function allele
(gene deletion) *6 (frame shift), *7, *8, • Homozygous carriers of two reduced
*11, *12, *13, *14, *15, *16, *19, *20, activity alleles
*21, *38, *40, *42 • Heterozygous carriers of a partially
Gene duplication have been active allele and a loss-of-function allele
reported for both *4 and *6 Poor metabolizers:
• Homozygous carriers of two loss-of-
Gene duplications/copy number Enhanced activity function alleles
variants Ultrarapid metabolizers:
*1, *2, *10, *17, *29, *35, *41, *43, *45 • Carriers of ≥3 active alleles
in Asians (about 0%–1% of population) and is converted by CYP2D6 to the pharmacologically

Africans (0%–5% of population) are lower than more active metabolite morphine. UMs adminis-
that reported for the Caucasians (5%–14% of tered the usual therapeutic dose of codeine have
population), the high prevalence of CYP2D6*10 been reported to exhibit symptoms of narcotic
and CYP2D6*17 in these two IM populations overdose associated with significantly elevated
provides a biologic and molecular explanation morphine concentrations. This toxicity poten-
for reported higher drug concentrations and/or tial had been highlighted in several case reports
the practice of prescribing lower dosage require- [25–29], including a fatal case of a breast-fed
ments in people of Asian and African heritage infant that was attributed to extensive formation
[16–19]. On the other hand, the UM phenotypic of morphine from codeine taken by the mother
frequency is much higher in Northeast Africa who is a UM [26]. (Table 1.2) Prior to this unfor-
and Oceania, including the Saudi Arabian (20%) tunate case, codeine has been considered safe
and black Ethiopian (29%) populations when for managing pain associated with childbirth, as
compared to Caucasians (1%–10%) and East literature reported low amounts of codeine are
Asians (0%–2%). usually found in breast milk. Therefore, this fatal
Even though accounting for a small percent case underscores the importance of understand-
of total CYP content in the liver, CYP2D6 medi- ing how genes can affect pharmacological and
ates the metabolism of approximately 20%–30% therapeutic outcome associated with exposure to
of currently marketed drugs, and CYP2D6 drug and/or active metabolite.
polymorphism affects significantly the elimina- Given the high incidence of codeine use
tion of 50% of these drugs [20], which include in postgestational women, Madadi et al. sub-
antidepressants, antipsychotics, analgesics, sequently performed a case-control study in
antiarrhythmics, antiemetics, and anticancer breast-fed infants with or without central ner-
drugs. Although differences in pharmacokinetic vous system depression signs and symptoms
parameters (elimination half-lives, clearances, after exposed to codeine during breast feedings.
and areas under the plasma concentration– They reported that breast-fed infants from moth-
time curves) for CYP2D6 substrates could be ers who are CYP2D6 UMs and homozygous car-
demonstrated among the different metabolic riers of UGT2B7*2 (rs7439366; UGT2B7 is a phase
phenotypes, the significant overlap in CYP2D6 2 enzyme involved in codeine glucuronidation)
activities in EMs and IMs result in therapeutic have an increased risk of potentially life-threaten-
implication mostly for the PM and UM phe- ing central nervous system depression [30]. Since
notypes. In the past, the clinical relevance of 2007, the Food and Drug Administration (FDA)
CYP2D6 polymorphism primarily concerned had issued several warning in revised prescrib-
the increased prevalence of ADRs in PMs ing information for codeine label. Citing the risk
administered standard doses of drugs that rely of morphine overdose in children and breast-fed
significantly on CYP2D6 for elimination. These infants and warnings from the FDA, the World
drugs include the antianginal agent perhexi- Health organization, Health Canada, and the
line (neuropathy) [21], the antiarrhythmic agent European Medicine Agency, the Academy of
propafenone (proarrhythmic events) [22], and Pediatrics had recently cautioned the use of
neuroleptic agents such as perphenazine (seda- codeine in children, regardless of age [31].
tion and parkinsonism) [23,24]. Samer et al. reported higher incidence of
More recently, occurrences of ADRs have also oxycodone toxicity in UMs that could be par-
been highlighted in UMs, primarily a result of a tially related to CYP2D6-mediated metabo-
10–30-fold increase in metabolite concentrations. lism to oxymorphone. The toxicity incidence
The most cited example is that of codeine, which is especially higher in those with concurrent
TABLE 1.2 Summary of Selected Literature on Impact of CYP2D6 Genotype and/or Drug Interaction on
Opioid Safety
Allelic Variants Reported Adverse Events References
Codeine CYP2D6*1 ×3 Life-threatening opioid intoxication exacerbated by drug [25]

interaction (with erythromycin and voriconazole) and
renal insufficiency
CYP2D6*2A/*2×2 Fatality in a breast-fed baby whose mother is a UM [26]
CYP2D6*1 ×N Fatality in a two-yr-old child due to respiratory arrest [27]
CYP2D6 ×2 Occurrence of apnea and brain injury in a 29-mo old child [28]
CYP2D6 gene duplication Fatality in two children who are UMs. Respiratory [29]
CYP2D6*1 ×N depression in an CYP2D6 EM who survived
Hydrocodone CYP2D6*2A/*41 Fatality in a child who also received concurrent [33]

clarithromycin
Oxycodone CYP2D6 UMs Greater toxicity, especially in those administered [32]

ketoconazole
Tramadol Heterozygous carrier of a 22-yr with a near-fatal case of cardiac arrest and high [34]
wild-type allele duplication concentration of tramadol metabolite
CYP2D6 gene duplication Tramadol-related respiratory depression [35]
ketoconazole administration [32]. Similarly, regard, the value of CYP2D6 genotype lies more
drug interaction with clarithromycin might have with guiding the choice of the appropriate anal-
played a role in the fatal case after hydrocodone gesic rather than genotype-based dosage recom-
exposure experienced by a 5-yr-old develop- mendation [13,38]. In particular, avoidance of
mentally delayed child with a CYP2D6*2A/*41 codeine, the only opioid analgesic with a Clinical
genotype [33]. In addition, tramadol cardio- Pharmacogenetics Implementation Consortium
toxicity and respiratory depression have been (CPIC) guideline, is recommended for PMs and
reported in UMs [34,35] with high level of the UMs. In addition, hydrocodone may not be a
active O-desmethyltramadol [34], which has good alternative analgesic agent to codeine in
been reported to exhibit a high correlation with these patient populations [13].
increased plasma epinephrine level [36]. The There are similar reports of lower efficacy in
FDA also recently updated its safety warning PMs with venlafaxine [39]. Another example is
for tramadol. tamoxifen, in which CYP2D6 plays a major role
In addition to implications for ADR, the effi- in the formation of the abundant and pharmaco-
cacy of prodrugs (such as codeine and hydro- logically more active metabolite, endoxifen [40].
codone) would also be reduced in PMs because Because endoxifen possesses greater affinity for
less parent drug is converted by CYP2D6 to the estrogen receptor than tamoxifen, PMs with
its respective active metabolite: morphine or the CYP2D6*4/*4 genotype have been shown to
hydromorphone, resulting in little analgesic have an increased risk of breast cancer recur-
relief [37]. However, despite strong evidence rence and worse relapse-free survival, as well as
of a genotype effect on the pharmacokinetics of a much lower incidence of moderate or severe
codeine and hydrocodone, the impact on dos- hot flashes [40]. The results of Kiyotani et al. [41]
age requirement is much less obvious. In this showed that the association between tamoxifen
response and CYP2D6 genotype in Japanese metabolically as PM during concurrent adminis-

breast cancer patients was only evident for those tration [49] which could have therapeutic sig-
patients receiving tamoxifen monotherapy, and nificance in patients taking multiple drugs. For
underscores the importance of considering con- example, it is not uncommon that tamoxifen-
comitant drug therapy in pharmacogenomics treated patients are also taking antidepressants
association study with tamoxifen and possibly such as selective serotonin reuptake inhibitors
other drugs. Conflicting data and continued (SSRIs), for both their antidepressant effect as
debate complicate the adoption of CYP2D6 well as their offlabel use to manage hot flashes.
genotyping in the therapeutic use of tamoxifen In view of the abundance and greater antiestro-
currently for patients with estrogen-receptor genic activity of endoxifen, concurrent admin-
positive breast cancer. Nevertheless, available istration of SSRIs that are potent inhibitors of
evidence strongly supports a role for CYP2D6 CYP2D6 (such as fluoxetine and paroxetine)
in pharmacological activation of tamoxifen [42] should best be avoided, and SSRIs with a lesser
and possibly a likelihood of lesser therapeutic extent of CYP2D6 inhibition (such as citalopram
benefit in PMs [43], with the ultimate impact on and venlafaxine) would be better alternate anti-
patient outcome to be tested in prospective clini- depressants if there is a need for concurrent anti-
cal studies. depressant therapy with tamoxifen.
Inadequate therapeutic response with impli- Interestingly, Gryn et al. described significant
cations for dosage adjustment had also been reduction in endoxifen concentration in a patient
demonstrated for UMs administered CYP2D6 with CYP2D6*1/*41 genotype. The reported
substrates. The best evidence described two endoxifen concentration was described as “well
patients with multiple copies of CYP2D6*2 below levels seen in most CYP2D6 poor metabo-
requiring the tricyclic antidepressant nortrip- lizers.” Although the case report did not inves-
tyline 500 mg daily (vs. usual recommended tigate the mechanism for the altered level, the
daily dose of 100–150 mg) in one patient [44] authors suggested it could be secondary to the
and clomipramine 300 mg/day (vs. 25–150 mg) patient’s concurrent treatment with phenytoin.
in another patient [9] to achieve adequate thera- Phenytoin is a potent inducer of multiple drug-
peutic response. Similarly, lower efficacy in UMs metabolizing enzymes as well as the efflux drug-
has been reported with other antidepressants transporter ABCB1 (also known as multidrug
[45,46] and antiemetics such as ondansetron [47]. resistance transporter, and described in more
Nevertheless, the therapeutic significance of details in later sections) [50], which mediates
CYP2D6 is not only impacted by genetic poly- the efflux transport of endoxifen [51]. Although
morphism but also by the potential of CYP2D6- the clinical outcome was not described, this
mediated drug–drug interaction, with clinical case underscores the importance of evaluating
implications in patients with different metabolic the modulating effect of drug interaction when
phenotypes resulting from competitive inhi- utilizing genotyping in individualized therapy
bition of CYP2D6. As shown by Hamelin and [52]. Similar modulating effects on other genes
colleagues [48], the pharmacological conse- encoding different metabolizing enzymes are
quences of drug–drug interaction via CYP2D6 described in later sections.
inhibition are of greater magnitude in EMs, In addition, it is important to realize that the
with pronounced and prolonged hemodynamic potential for drug interaction via CYP2D6 inhi-
responses to metoprolol, than in PM. bition could also be affected by the basal meta-
Potent CYP2D6 inhibitors had been shown bolic activity of the individual patient. We have
to reduce the metabolic capacity of EMs sig- shown that the UM phenotype could affect the
nificantly so that individual EM could appear potential for drug interaction with paroxetine, a
CYP2D6 substrate as well as a potent CYP2D6 is that, similar to CYP2D6 polymorphism, a
inhibitor, whence a UM with three functional “gain of function” CYP2C19*17 allele (c.-806C>T
CYP2D6 copies had undetectable paroxetine rs12248560) was identified in the 5′-flanking
concentration with standard dosing and showed region of CYP2C19, with increased gene tran-
no inhibitory effect at CYP2D6 [53]. scription associated with high enzyme activity
and an EM phenotype [54].
CYP2C19*2 and *3 are commonly found in
CYP2C19
Asians, with allele frequencies of about 30% and
CYP2C19 is located on chromosome 10q23.33 approximately 10%, respectively. In contrast, the
and is a large gene consisting of 90,209 nucleo- allele frequency of *3 is <1% in Caucasians and
tides and yet coding for CYP2C19 that contains African Americans, even though the *2 occurs
only 490 amino acids. Compared to the CYP2D6 at a frequency of about 13% and approximately
polymorphism, polymorphisms in the CYP2C19 18%, respectively, in these two ethnic groups.
gene do not affect as many drugs, and their clini- About 50% of the Chinese population possess
cal implication has not been extensively evalu- either the *1/*2 and *1/*3 genotypes, and 24%
ated. However, studies involving the proton have the *2/*2, *2/*3, or *3/*3 genotypes [55]. In
pump inhibitors (PPIs) provide extensive phar- contrast, only about 2%–5% and 30%–40% of
macokinetic and clinical evidence, as well as the the Caucasian population, respectively, have the
economic impact of the importance of taking *2/*2 and *1/*2 genotypes. Similar frequencies of
into consideration of CYP2C19 polymorphism in the heterozygous and homozygous variant geno-
the management of gastroesophageal diseases. types are reported in persons of African descent.
Over the years, as many as 30 CYP2C19 alleles, The higher prevalence of PMs and heterozy-
including those with no functional activity (*2, gote EMs carrying defective CYP2C19 alleles in
*3, *4, *6, *7) and those associated with reduced Asians likely account for reports of slower rates
catalytic activity (*5 and *8), have been identified of metabolism of CYP2C19 substrates and the
(www.cypalleles.ki.se/cyp2c19.htm). The prin- practice of prescribing lower diazepam dosages
cipal null alleles are *2 (c.681G>A, rs4244285) for patients of Chinese heritage [56,57]. An oppo-
and *3 (c.636 G>A, rs4986893), resulting in an site direction in ethnic variation was observed in
inactive CYP2C19 enzyme, and accounting the prevalence of CYP2C19*17 (18% in Swedes
for the vast majority of the PM phenotype in and Ethiopians vs. 4% in Chinese), with the
Caucasians (1%–6%), black Africans (1%–7.5%), *1/*17 and *17/*17 genotypes occurring in more
and Asians (10%–25%). Genotyping these two Caucasians and Ethiopians (up to 36%) than
defective alleles has been shown to detect about Asians (8% of Chinese and 1% of Japanese) [54].
84%, greater than 90%, and about 100%, of PMs CYP2C19 accounts for about 3% of total hepatic
in Caucasians, Africans, and Asians, respec- CYP content, and CYP2C19 polymorphism
tively. The detection rate for Caucasians PMs affects the metabolism of PPIs (omeprazole, lan-
could be increased to about 92% by includ- soprazole, pantoprazole, rabeprazole), antide-
ing the less common CYP2C19*4 (rs28399504) pressants (citalopram, sertraline, moclobemide,
and CYP2C19*6 (rs72552267) in the genotyping amitriptyline, clomipramine), the antiplatelet
assay. Similar to other CYP2C19 rare variants, *5 agent clopidogrel, the antifungal drug voricon-
(rs56337013), *7 (rs72558186), and *8 (rs41291556) azole, the benzodiazepine diazepam, and the
have <1% allele frequency. Individuals carry- anticancer drug cyclophosphamide. Similar to
ing at least one functional allele are referred as CYP2D6, CYP2C19 is also susceptible to inhi-
EMs, whereas those with one functional and bition by drugs such as cimetidine, fluoxetine,
one loss-of-function allele are IMs. Of interest and diazepam. The inhibition occurs in a gene
dose-dependent manner in which carriers of two effectiveness of pharmacogenomics-guided dos-

CYP2C19*17 alleles exhibit the greatest extent of ing when compared to conventional dosing [69].
inhibition compared to little to no inhibition for On the other hand, despite increased metabo-
patients with CYP2C19 PM phenotype. lism of PPI in carriers of CYP2C19*17 and the
The PPIs and clopidogrel provide the best potential of therapeutic failure [54,70], eradica-
examples of clinical relevance of CYP2C19 tion rates of H. pylori have so far not to be shown
polymorphism. When compared to EMs, PMs to be associated with the CYP2C19*17 allele, at
showed 5- to 12-fold increases in the area under least for patients with peptic ulcer disease and
the curve (AUC) of omeprazole, lanzoprazole, receiving the triple regimen of pantoprazole,
and pantoprazole [58,59], whereas homozygous amoxicillin, and metronidazole [67,71].
carriers of the CYP2C19*17 were shown to have In healthy volunteers given a single 200-mg
a modest 2.1-fold lower AUC than EMs [60]. In dose of voriconazole, Wang et al. demonstrated
addition, the CYP2C19 genotype significantly a 48% lower AUC in heterozygous carriers of
affects the achievable intragastric pH with PPI the CYP2C19*17 allele as compared to homozy-
therapy. In subjects who took a single 20-mg gous carriers of CYP2C19*1 [72]. This finding is
dose of omeprazole, Furuta et al. showed a good consistent with data that is more recent show-
relationship not only between CYP2C19 geno- ing correlation between CYP2C19 polymor-
type and AUC, but also between the genotype phism and target voriconazole concentrations,
and achievable intragastric pH: 4.5 in PMs, 3.3 with an increased risk of subtherapeutic trough
in heterozygous EMs, and 2.1 in homozygous concentration in patients with the CYP2C19
EMs [61]. Given the smaller dependency of UM phenotype [73–75]. Investigators have
esomeprazole and rabeprazole on CYP2C19 for also shown 42% lower escitalopram concentra-
metabolism, the pharmacological action of these tions and 21% lower AUC in patients who are
two PPIs is less affected by the CYP2C19 poly- homozygous carriers of CYP2C19*17 when com-
morphism [62,63]. pared to CYP2C19*1 homozygotes [76]. Clearly,
An important treatment strategy in the man- CYP2C19*17 homozygotes might require higher
agement of patients with peptic ulcer disease doses of most CYP2C19 substrates, including
is eradication of Helicobacter pylori with a regi- PPIs [60,70], antidepressants, and voriconazole
men of PPI and antibiotics. CYP2C19 genotype- [72]. However, despite the presence of pharma-
related pharmacological effects have also been cokinetic differences, the impact of CYP2C19*17
associated with improved eradication rate of H. on therapeutic outcomes with these CYP2C19
pylori after dual [64] or triple therapy including substrates have not been evaluated extensively
omeprazole [65], lansoprazole [66], or panto- or confirmed.
prazole [67]. The cure rate achieved with dual- Clopidogrel is an antiplatelet prodrug that
and triple-therapy regimens was 100% in PMs requires CYP2C19-mediated conversion to its
compared with 29%–84% in EMs [64–67]. Furata active metabolite for therapeutic effect [77], with
et al. also reported a much higher eradication most of pharmacokinetic and pharmacody-
rate of 97% in EMs who failed initial triple ther- namic evidence related to the CYP2C19*2 allele
apy (lansoprazole, clarithromycin, and amoxi- [77–82]. Shuldiner et al. conducted a GWAS in
cillin) and subsequently were retreated with which ex vivo adenosine diphosphate (ADP)-
high-dose lansoprazole (30 mg four times daily) induced platelet aggregation at baseline and
and amoxicillin [68]. In addition, to showing a after 7 days of clopidogrel were measured in a
gene-dose effect in achieving desirable ranges of genetically homogenous cohort of 429 healthy
intragastric pH and H. pylori cure rates for lanso- Amish subjects. In addition, 400,230 SNPs were
prazole, Furuta et al. also demonstrated the cost evaluated in each subject for association with
platelet activity. They reported that the SNP significant number of low-risk patients, such as
rs12777823 on chromosome 10q24 with the those with acute coronary syndrome managed
greatest association signal is in strong LD with medically or patients with atrial fibrillation
CYP2C19*2, accounting for 12% of the interindi- [93,94]. The meta-analysis of Hulot et al. [92]
vidual variation in platelet aggregation during also evaluated the drug interaction potential of
clopidogrel treatment. As importantly, there was PPIs because of their inhibitory effect toward
no association between the CYP2C19 polymor- CYP2C19, resulting in a metabolic phenotype
phism and baseline platelet aggregation [83]. of CYP2C19 PM similar to that of carriers of the
The results from this GWAS confirmed results *2 allele. Both Hulot et al. and another study
from previous candidate gene studies regard- [92,95] suggest that the detrimental effects of
ing the role of CYP2C19 as a major genetic PPIs on cardiovascular outcomes with clopido-
determinant of clopidogrel response [78–82]. grel likely occur at a higher frequency in high-
In a follow-up study of 227 patients undergo- risk patients receiving both drugs. Current data
ing percutaneous coronary intervention (PCI), do not provide sufficient information to deter-
the investigators also reported a higher inci- mine whether the observed adverse effects of
dence of cardiovascular death in carriers of the PPI usage in high-risk patients (e.g., patients
*2 allele (20.9% vs. 10%) at 1-yr follow-up. No undergoing PCI) are related to CYP2C19 inhibi-
association with response was found for other tion or yet-to-be-discovered mechanisms.
CYP2C19 alleles, including *3, *5 (rs56337013), Based on the increasing amount of litera-
and *17, that were also genotyped in the study ture data supporting an association between
[83]. A recent meta-analysis confirms the asso- CYP2C19*2 and poor clopidogrel response, the
ciation of the CYP2C19 nonfunctional allele and FDA has made several revisions to the approved
high-risk of adverse cardiovascular events in product label of clopidogrel. Although the March
patients who underwent PCI [84]. 2010 version specifically addresses the implica-
Although the increased production of the active tion for homozygotes, there is no guidance on
clopidogrel metabolite in carriers of the *17 allele the implication for heterozygotes. In addition,
has been associated with greater inhibition of as with other revised labels with additional
platelet aggregation [85,86] and better clinical out- genetic information, there is little guidance on
comes [87], there is also the potential of increased clinical management of carriers of CYP2C19*2.
bleeding risk [88]. In addition, the increased The September 2016 label warns of diminished
response of the *17 allele has been suggested not effectiveness in CYP2C19 poor metabolizers
as a direct effect, but rather attributed to that of and suggests the use of different platelet P2Y12
the *1 allele [89]. Given this consideration, there inhibitors in those patients. In light of the scien-
is no specific therapeutic recommendation for this tific and clinical evidences as well as the regu-
gain-of-function allele in the most recent practice latory decision, several recent clinical studies
guideline for CYP2C19 genotyping [90]. addressing alternative antiplatelet agents have
Even with involvement of other non-genetic been initiated and are discussed in Chapter 6.
factors [91], the increased risks of major adverse
cardiovascular events and stent thrombosis in
CYP2C9
carriers of at least one CYP2C19*2 allele were
confirmed in two meta-analyses that included In addition to CYP2C19, another important
almost 22,000 patients [88,92]. Differences in member of the CYP2C subfamily of enzymes
patient selection for analysis likely account is CYP2C9 containing 490 amino acids. It is
for the lack of association reported in two encoded by CYP2C9 consisting of 50,708 nucleo-
other recent meta-analyses, which included a tides and located on chromosome 10q24.1 in close
proximity to CYP2C19. To date, approximately 60 and the S-isomer of warfarin; oral antidiabetic
CYP2C9 alleles (www.cypalleles.ki.se/cyp2c9. agents such as glibenclamide, glimepiride, glipi-
htm) have been identified in the regulatory zide, glyburide and tolbutamide; antiepileptic
and coding regions of CYP2C9, with CYP2C9*2 agents such as phenytoin, and antihypertensive
(c.430C>T, rs1799853) and CYP2C9*3 (c.1075A>C, agents such as candesartan, irbesartan, and losar-
rs1057910) being the most common in persons of tan. The enzyme reduction associated with the *3
European descent and the most extensively stud- allele is greater than that with the *2 allele, with
ied. Both reduced-function alleles exhibit single a 5- to 10-fold reduction in homozygous *3 car-
amino-acid substitutions (p.R144C and p.I359L, riers and two-fold reduction in heterozygous *3
respectively) in the coding region, accounting carriers, when compared to homozygous *1 carri-
for lower enzyme activity by approximately 30% ers. For example, clearance of warfarin is reduced
for *2 and 80% for *3 [96]. Other reduced-func- by 90%, 75%, and 40% in subjects with the corre-
tion alleles of potential importance included *5 sponding CYP2C9 genotypes of *3/*3, *1/*3, and
(rs28371686), *6 (rs9332131), *8 (rs7900194), and *1/*2 [101]. respectively. Interestingly, the effects
*11 (rs28371685). [97–100] In addition, a “gain-of- of several reduced-function alleles appear to be
function” CYP2C9 (rs7089580) variant in intron 3 substrate dependent. For the *2 allele, a signifi-
has been identified [97]. cant effect was shown for clearances of aceno-
Significant variations in CYP2C9 alleles and coumarol, tolbutamide, and warfarin but not for
genotype frequencies exist among different other substrates. On the other hand, nonsteroidal
ancestry groups. Both CYP2C9*2 and CYP2C9*3 anti-inflammatory drug (NSAID)-associated gas-
are more common in Caucasians (11% and 7%, trointestinal bleeding was shown to be related
respectively) than in Asians and Africans. In to the *3 but not the *2 variant [102]. Similarly,
fact, CYP2C9*2 has not been detected in Asians, although the *8 allele has no effect on clearance of
in whom CYP2C9*3 is the most common allele. losartan, it decreases enzyme activity of warfarin
On the other hand, CYP2C9*8, as well as *5, and phenytoin, and exhibits an increased activity
*6, and *11 (albeit all at a lower frequency than toward tolbutamide [103].
8), are present almost exclusively in African Of all of the CYP2C9 substrates, warfarin is the
Americans. The novel CYP2C9 c.18786A>T vari- most extensively studied with dosing implica-
ant (rs7089580) was reported to occur in about tions for different metabolic phenotypes. CYP2C9
40% of the African American population, and polymorphism, together with the literature infor-
CYP2C9*8 (c.449G>A, rs7900194) appears to be a mation regarding the gene that encodes the war-
major contributor to CYP2C9 expression in this farin target, vitamin K epoxide reductase complex
ethnic group [97]. Approximately 1% and 0.4% (VKORC1) [104], provide promising translational
of Caucasians have the *2/*2 and *3/*3 geno- use of the pharmacogenomic data [105,106], with
types, respectively. The *1/*3 genotype occurs at revised language regarding their impact incorpo-
a frequency of 4% in the Chinese and Japanese rated into the drug label [107]. CYP2C9 mediates
populations, with almost complete absence of the conversion of the active S-enantiomer of war-
the other genotypes (*2/*2, *2/*3, *1/*2, and *3/*3). farin to an inactive metabolite. Most of the data
CYP2C9 accounts for about 20% of total document that the *2 and *3 alleles are associated
hepatic CYP content and is involved in the metab- with greater difficulty with warfarin induction
olism of about 10% of currently marketed drugs. therapy, increased time to achieve stable dos-
These CYP2C9 substrates include the nonsteroi- ing, lower mean-dose requirement (e.g., as low
dal antiinflammatory drugs such as celecoxib, as ≤1.5 mg/day with *3/*3), as well as increased
ibuprofen, and flurbiprofen; oral anticoagulants risks of elevated , international normalized ratios
such as acenocoumarol, and phenprocoumon, (INRs) and bleeding [105,108,109]. Giving the 30%
and 80% difference in enzyme activity reduction Caucasians (with the *4 variant reportedly only
between the *2 and *3 alleles, the warfarin-dose found in Caucasians). On the other hand, *2 and
requirements differ between carriers of these two a rare allele, *5 (rs72558196, frame-shift deletion)
alleles. Compared to homozygous carriers of the are exclusively found in Africans and Japanese,
*1 allele, data suggest a dose reduction of 30% and respectively [116,117].
47% for patients with the heterozygous genotypes Accounting for about 7% of total hepatic con-
of CYP2C9*1/*2 and CYP2C9*1/*3, respectively, tent, the hepatic expression level of CYP2C8 lies
and up to 80% for patients with the homozygous between that of CYP2C19 and CYP2C9 [118], and
CYP2C9*3/*3 genotype [106,108,110,111]. it plays an important role in the metabolism of
In addition, with the difference in allele prev- different drugs, primarily the antidiabetic agents
alence among different ancestral groups, the (pioglitazone, repaglinide, rosiglitazone, and tro-
strength of association between the *2 and *3 glitazone), the anticancer agents (paclitaxel), the
alleles and genotypes is stronger in Caucasians antiarrhythmic drug amiodarone, and the anti-
[112,113]. Other recently identified alleles (*5, *6, malarial agents amodiaquine and chloroquine.
*8, and *11) have been reported to better predict The smaller number of substrates as compared
dose requirement (20% lower for *8 carrier) and to CYP2C9 and CYP2C19 presumably leads to
adverse outcomes in African Americans [97– the lesser interest in studying CYP2C8 polymor-
99,103,112,114]. On the other hand, the “gain- phism. As a result, the molecular mechanisms
of-function” CYP2C9 c.18786A>T allele was underlying interindividual variations in CYP2C8
reported to contribute a higher-dose require- activity remain unclear. Decreased elimination
ment (3.7 mg/week/allele) [97]. Finally, concur- of R-ibuprofen has been reported in carriers of
rent drugs with significant modulating effect CYP2C8*3 [119,120]. However, with the pres-
on CYP2C9 activity would also have an impact ence of a strong LD between CYP2C8*3 and
on the association between CYP2C9 genotypes CYP2C9*2 [119,121], the individual contribution
and warfarin-dose requirement [115]. The effect of CYP2C8*3 remains to be elucidated. In con-
of CYP4F2 and VKORC1 genotypes on warfarin trast, increased metabolism of repaglinide was
pharmacokinetics and pharmacodynamics will reported in heterozygous carriers of CYP2C8*3
be discussed in later sections of this chapter. when compared to carriers of either *1 or *4 [122].
Although this finding is interesting, other reports
showed that genetic polymorphism of the hepatic
CYP2C8 uptake transporter plays a more important role in
In addition to CYP2C9 and CYP2C19, the determining repaglinide pharmacokinetics [123].
other clinically relevant members of the highly The identification of two CYP2C8 haplotypes: a
homologous genes (CYP2C18–CYP2C19– high-activity allele associated with CYP2C8*1B
CYP2C9–CYP2C8) that cluster on chromosome and a low activity associated with CYP2C8*4
10q24 [83] is CYP2C8. To date, several SNPs [124], further highlights the need to characterize
within the coding region of the CYP2C8 gene the different CYP2C8 variants, including their
have been identified (www.cypalleles.ki.se/ functional relevance.
cyp2c8.htm). The more common variants are
*2 (c.805A> T, rs11572103, resulting in p.I269F),
*3 with two amino acid substitutions (c.416G
CYP3A4/5/7
>A, rs11572080 with p.R139K, and c.1196A >G, A total of four CYP3A genes have been
rs10509681 with p.K399R) reportedly to be in described in humans: CYP3A4, CYP3A5,
total LD, and *4 (c.792C >G, rs1058930, p.I264M). CYP3A7, and CYP3A43; with CYP3A7 primar-
Both *3 and *4 alleles are more common in ily important in fetal CYP3A metabolism and
CYP3A43 exhibiting little functional or clinical current consensus is that CYP3A4 polymorphisms
relevance. More than 20 variants in the cod- are mostly of minor clinical relevance, and unlikely
ing region of CYP3A4, most of them associated responsible for the 10- to 40-fold interindividual
with reduced catalytic activity of the enzyme, variations in CYP3A4 activities. This is likely a
have been identified to date. [125] The signifi- result of low variant allele frequencies, only small
cance of the reduced-function allele CYP3A4*22 changes in enzyme activity in the presence of a
C>T SNP (rs35599367) in intron 6, which results variant allele, as well as the overlapping substrate
in 20% decrease in enzyme activity, has been specificity between CYP3A4 and CYP3A5. The
extensively evaluated recently, especially in con- significant variability in CYP3A4 activity is more
junction with CYP3A5 SNP [126–129]. CYP3A5 likely related to a large number of drugs capable
expression is highly polymorphic with the loss- of altering the enzyme through induction or inhi-
of-function *3 allele (c.6986A>G, rs776746) in bition in the liver and the gastrointestinal tract.
intron 3 as the most common variant, which Therefore, there is currently no uniform agreement
results in a splicing defect and absence of on metabolizer subgroups for CYP3A4.
enzyme activity. Other loss-of-function and On the other hand, the clinical relevance of
reduced-function CYP3A5 variants include CYP3A genetic polymorphism is primarily
the *2 (rs28365083; g.27289C>A; T398N), *6 associated with CYP3A5. The pharmacokinet-
(14690G>A; rs10264272), and *7 (rs41303343; ics of the immunosuppressive agent tacrolimus
27131_27132ins T) alleles [130,131]. is dependent on the CYP3A5 genotype, with a
In general, CYP3A4 polymorphism is more higher-dosage requirement in homozygous or
common in Caucasians, with *2 and *7 being heterozygous carriers of CYP3A5*1 [134,135]. In
the more prevalent alleles, whereas Asians have addition, results from a randomized controlled
higher frequencies of *16 and *18 variants. Of trial showed that pharmacogenetic-guided dos-
note, is that CYP3A4*22 is absent in both Asian ing based on CYP3A5 genotype was associated
and African populations. Carriers of the wild- with greater achievement of target tacrolimus
type CYP3A5*1 allele (also known as CYP3A5 concentrations when compared to standard dos-
“expressors”) are more common in Asians (up to ing based on body weight [136]. Nevertheless,
50%) and Blacks (up to 90%) than in Caucasians the overall clinical relevance of CYP3A5 poly-
(about 15%). The allele frequency of CYP3A5*3 morphism is limited by its small contribu-
is much higher in Caucasians and Asians, occur- tion (2%–3%) to the total CYP3A metabolism.
ring in 90% and 75% of the populations, respec- [137,138], and reportedly impacted by timing
tively, versus a relatively low frequency of 20% of tacrolimus therapy. In a meta-analysis of
in Africans. On the other hand, both CYP3A5*6 tacrolimus-dose requirement and rejection rate,
and *7 are absent in Caucasians and Asians Tang et al. indicated that the effect of CYP3A5
but present in Africans with frequencies up to polymorphism (CYP3A5*3) is most prominent
17% [130,132,133]. The CYP3A5*2 allele has a during the first month of tacrolimus therapy,
frequency of less than 1% in Caucasians and is suggesting that CYP3A5 genotyping might be
mostly absent in other ethnic populations. useful to guide initial dosing of tacrolimus for
CYP3A4 accounts for about 40% of the total prevention of early graft rejection [139]. Inclusion
hepatic CYP content and mediates the metabolism of both CYP3A4*22 and CYP3A5*3 status have
of more than 50% of currently used drugs with been shown in many recent studies to signifi-
many examples from the pharmacological classes cantly improve tacrolimus dose prediction [126–
of macrolide antibiotics, antidepressants, anti- 129,140]. Therapeutic and pharmacogenomic
psychotics, anxiolytics, calcium channel blockers, recommendations for tactolimus were included
immunosuppressants, opiates, and the statins. The in the recent CPIC guideline [141].
On the other hand, despite significant effect carriers of the V allele [148]. However, additional
of CYP3A4*1G (g.20230G>A, rs2242480) and studies demonstrated the association between
CYP3A5*3 on ticagrelor pharmacokinetics in a the CYP4F2 genotypes and dose requirements in
recent study of healthy Chinese subjects, there Caucasians and Asians [144,147,149,150] but not
was no association on the extent of inhibition in African Americans, Egyptians, or Indonesians
of platelet aggregation. Therefore, the investi- [114,145,146]. This could reflect ethnic differ-
gators concluded that no dosage adjustment ences in CYP4F2 allele and genotype frequencies
based on CYP3A4 and CYP3A5 genotypes is distribution, the minor contribution of CYP4F2
necessary [142]. [151], as well as the modulating effects of other
more important dose-requirement variables
such as CYP2C9 and VKORC1.
CYP4F2
There are six members within the CYP4F gene
CYP2B6
subfamily residing on chromosome 19p13.1-2:
CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, Although several variant alleles with low
and CYP4F22. The importance of CYP4F2, a enzyme expression, including CYP2B6*6 and
vitamin-K oxidase, is related to the recent report *18, have been identified, to date there have not
of its role in mediating the conversion of vita- been any reports of the presence of an impor-
min K1 to hydroxyvitamin K1. Increased CYP4F2 tant loss-of-function allele. Among the variant
activity causes decreased activation of vitamin alleles, the CYP2B6*6 haplotype carrying two
K-dependent clotting factors, reflecting the nonsynonymous SNPs (c.516G>T, rs3745274
consequence of reduced availability and reduc- and c.785A>G, rs2279343 causing two amino
tion of vitamin K1 to vitamin KH2 necessary acid changes: p.Q172H and p.K262R, respec-
for carboxylation and activation of the clotting tively) in exon 4 is the most common and occurs
factors. On the other hand, the g.7253233C>T commonly in Caucasians and Asians (16%–
(rs2108622, p.V433M) SNP in exon 2 of the 26% allele frequency), whereas*18 (c.983T>C,
CYP4F2 gene results in lower protein expression rs28399499, I328T) is more common in Black
and enzyme activity, and consequently greater subjects with allele frequencies of 7%–9% [152].
vitamin K1 availability [143,144]. The T allele Interestingly, the 785A>G SNP resulting in
at rs2108622 confers the CYP4F2*3 designation. the K262R amino acid change also occurs as a
Some ethnic differences in the V433M SNP has separate allele, CYP2B6*4 (rs2279343 without
been reported, with the M433 allele occurring at rs3745274), and results in increased expres-
a much lower frequency in African Americans sion and enzyme activity [153,154]. Whether
[114], which contrast with its high occurrence in the 516G>T and 785A>G mutations are linked
Indonesians and Egyptians [145,146]. to additional mutations creating specific haplo-
Although genome-wide association studies types causing either high or low CYP2B6 activi-
enable detection of weaker genetic signals [144], ties is not known. Gatanaga et al. also reported a
CYP4F2 genotype nevertheless only accounts new *26 allele containing 499G for the c.499C>G
for 1%–3% of the overall variability of warfa- SNP (rs3826711), and 499G always coexists with
rin-dose requirement [144,147], in contrast to 516G>T and 785A>G, thus representing a novel
CYP2C9 genotype that accounts for approxi- haplotype containing the 499C>G, 516G>T and
mately 10%–12% of the variability. Homozygous 785A>G SNPs [155].
carriers of the M allele of the p.V433M SNP had CYP2B6 accounts for up to 6%–10% of total
been shown to require an approximate 1 mg/ CYP content in the liver [156,157], and known
day higher dose of warfarin than homozygous substrates include anticancer drugs such as
cyclophosphamide and ifosfamide, the smok- genotyped for different SNPs, including the
ing cessation agent bupropion, the antiretrovi- 499C>G, 15631G>T and 18053A>G polymor-
ral agents efavirenz and nevirapine, as well as phisms [155]. All patients received the standard-
methadone. In addition to reduced activation of dosage regimen of 600 mg/day, and extremely
cyclophosphamide leading to lower antitumor high concentrations (9,500 ± 2,580 ng/mL)
efficacy, CYP2B6 gene variants play a significant were obtained in all 14 patients with the
role in determining bupropion and methadone CYP2B6*6/*6 genotype and in both patients
pharmacokinetic variabilities, in particular with with the CYP2B6*6/*26 genotype. In contrast,
CYP2B6*6 (decreased clearance) [158–160] and only two patients with other CYP2B6 geno-
CYP2B6*4 (increased clearance) [159]. Levran types had similarly high efavirenz concentra-
et al. reported that the mean daily methadone tions, and both were heterozygous carrier of
dose in heroin addicts was 88 and 96 mg, respec- either the *6 allele (7,140 ng/mL) or *26 allele
tively, for homozygous carriers of variant alleles (9,710 ng/mL). Therefore, the *6 and *26 alleles
785A>G and 516G>T; as compared to 133 and were both associated with high efavirenz con-
129 mg, respectively, for heterozygous carriers centrations, and patients with the CYP2B6*6/*6
of the two variant alleles; and 150 and 151 mg, or the CYP2B6*6/*26 genotype had the highest
respectively, for wild-type homozygotes [161]. concentrations with standard-dosage regimen
In individuals whose death was attributed to of 600 mg/day.
methadone poisoning, CYP2B6*4, *6, and *9 To investigate the feasibility of dose reduction
alleles were associated with higher postmortem in patients with high efavirenz concentrations sec-
methadone blood concentrations (P ≤ .05) [162]. ondary to CYP2B6 polymorphism, the investiga-
However, despite report of longer corrected QT tors then reduced the efavirenz-dosage regimen
interval (QTc) interval in CYP2B6 slow metabo- to 400-mg/day in five patients and to 200 mg/day
lizers [163], a clear relationship between CYP2B6 in another seven patients. The genotypes in these
genotype and risk of cardiac arrhythmia and 12 patients included nine *6/*6 homozygotes,
sudden death remains to be determined. two *6/*26 heterozygotes, and one *1/*26 hetero-
The potential clinical relevance of CYP2B6 zygote. The plasma concentrations decreased
has been evaluated primarily with the nonnu- proportionally with the dose reductions. Despite
cleoside reverse transcriptase inhibitors efavi- receiving the lower-dosage regimens for more
renz and nevirapine. Increased central nervous than 6 months, the 12 patients were able to main-
system side effects associated with variable sys- tain therapeutically effective anti-HIV-1 activity
temic exposure of efavirenz could be the result with HIV-1 load continuously less than 50 cop-
of patients being carriers of the *6 or *18 alleles ies/mL. Central nervous system side effects were
[155,164]. Incorporating determination of addi- reported to be much less frequent at the lower-
tional less-frequent alleles such as *26 and *29 dosage regimens. Similar therapeutic success
could further improve the prediction of elevated with persistent suppressed HIV-1 load was also
plasma efavirenz concentrations [155,164,165]. demonstrated in efavirenz-naïve patients (*6/*6
Altered concentrations of, and clinical outcome and *6/*26), who were administered the lower-
associated with, nevirapine have also been asso- dosage regimen of 400-mg/day. The overall study
ciated with CYP2B6 rs3745274 SNP. results demonstrated the feasibility of genotype-
In a prospective study of the effect of CYP2B6 based efavirenz-dose reduction in patients with
polymorphism on efavirenz concentrations and CYP2B6 *6/*6 and *6/*26 genotypes, with addi-
exposure, 456 patients infected with the human tional advantages of less central nervous system
immunodeficiency virus type 1 (HIV-1) were side effects and lower treatment cost.
CYP2A6 CYP1A2
CYP2A6 only accounts for about 4% of total Located on chromosome 15, CYP1A2 con-
CYP450 content, and significant variations sists of 7,758 nucleotides and encodes the
in CYP2A6 activity are primarily a result of enzyme CYP1A2 that contains 516 amino acids.
genetic influence. The CYP2A6 gene is located Polymorphisms of the CYP1 family of genes
on chromosome 19 and codes for the pro- have been studied for association with cancer
tein CYP2A6 consisting of 494 amino acids. susceptibility. Several CYP1A2 SNPs have been
With more than 40 variants identified, the identified, including CYP1A2*1C (rs2069514,
primary variants for CYP2A6 polymorphism –3860G>A) and the haplotype CYP1A2*1K con-
(www.cypalleles.ki.se) include CYP2A6*2 taining three variants: –739T>G (rs2069526),
(rs1801272, g.1799T >A), CYP2A6*4 (gene dele- –729C>T (rs12720461), and –163C>A (rs762551).
tion), CYP2A6*5 (rs5031017 g.6582G > T), and However, to date there has been no consistent
CYP2A6*20 (rs28399444, frame shift), all of report of any functional CYP1A2 alleles that
which are associated with abolished enzyme result in important changes in gene expression
activity. Additional alleles associated with and enzyme activity. Therefore, in contrast to
reduced enzyme activity include *7 (rs5031016, other CYP isoenzymes such as CYP2C19 and
g.6558 T>C), *10 (rs28399468, g.6600G>T) *11 CYP2C9, there is less agreement in the litera-
(rs111033610. g.3391T>C), *17 (rs28399454, ture regarding acceptable method of defining
g.5065G>A), *18 (rs1809810 g.5668A>T), and CYP1A2 metabolic phenotype by CYP1A2
*19 (rs5031016 g.6558T>C). As with other CYP genotype.
polymorphisms, there are substantial inter- Nevertheless, a unique aspect of the CYP1A2
ethnic differences in allele frequency. Deletion gene is that a specific allele, CYP1A2*1F
of the CYP2A6 gene is very common in Asian (rs762551) containing a c.-163C>A mutation in
patients [166], which likely accounts for the intron 1, has been shown to affect CYP1A2 induc-
dramatic difference in the high occurrence of ibility [167] and the magnitude of increased
PMs in Asian (20%) versus Caucasian popula- caffeine metabolism in smokers [168,169].
tions (≤1%). However, conflicting reports have been reported
Nicotine is metabolized by CYP2A6 to for other CYP1A2 substrates [170–172]. This
cotinine, and the clinical relevance of the gene–environment interaction makes genotype–
CYP2A6 polymorphism has been primar- phenotype prediction of phenotype much more
ily investigated in managing patients with difficult. Finally, promoter variation is less likely
tobacco abuse. Nonsmokers were found to be to result in substrate-dependent effects, and the
more likely to carry defective CYP2A6 alleles functional importance of increased CYP1A2
such as *7 and *9 than were smokers. In addi- inducibility is currently unknown.
tion, smokers with defective CYP2A6 alleles CYP1A2 contributes up to 10% of the total
smoked fewer cigarettes and were more likely hepatic P450 content. However, unlike other CYP
to quit. These results likely reflect higher isoenzymes, it only mediates the metabolism
nicotine concentrations, enhanced nicotine of several commonly used drugs such as olan-
tolerance and increased adverse effects from zapine, clozapine, duloxetine, and theophylline
nicotine in CYP2A6 poor metabolizers. Based [173,174]. Although pharmacokinetic studies
on these observations, CYP2A6 inhibition evaluating CYP1A2 inducibility by smoking or
may have a role in the management of tobacco omeprazole have been performed, none of the
dependency [166]. studies have produced consensus information.
POLYMORPHISMS IN NON-CYP450 thrombopoietin receptor agonist for the man-

DRUG-METABOLIZING ENZYMES agement of thrombocytopenia).
Irinotecan, also known as CPT-11, is a pro-
Genetic polymorphisms in many non-P450 drug that requires metabolic activation via
enzymes also play a role in influencing metabo- carboxylesterase to SN-38, a potent inhibitor
lism and elimination of many drugs. Among of topoisomerase I. SN-38 is inactivated via
these enzymes, UDP-glucuronosyl transferase glucuronidation by the polymorphic UGT1A1
(UGT), thiopurine-S-methyltransferase (TPMT), enzyme. Both UGT1A1*28 and *6 had been
dihydropyrimidine dehydrogenase (DPD), associated with impaired SN-38 glucuronida-
N-acetyltransferase (NAT), and glutathione-s- tion, especially in patients who are homozy-
transferase (GST) have been characterized and gous carriers (UGT1A1*28 TA7/TA7) [176,177].
their clinical relevance studied. The ensuing high SN-38 concentrations lead to
increased SN-38 excretion into the gut lumen,
predisposing patients to severe diarrhea even
UDP-Glucuronosyl Transferase
with standard irinotecan-dosage regimens.
The uridine diphosphate (UDP)-glucuronosyl Abnormally high SN-38 concentrations have
transferase (UGT) enzymes are divided into two also been reported in patients with severe neu-
distinct subfamilies: UGT1 and UGT2. UGT1A1 tropenia [178]. These pharmacogenetic-related
has been the most extensively investigated adverse reactions have also been demonstrated
among the UGT1A enzymes. A polymorphism in prospective clinical trial [179] that led to FDA
with an extra thymine-adenine (TA) repeat approval of the Invader UGT1A1 Molecular
(TA insertion) in the 5′-promoter region of the Assay (Third Wave Technologies) for genotyp-
UGT1A1 gene results in the (TA)7TAA allele or ing UGT1A1 alleles and revision of the irinote-
UGT1A1*28 (rs8175347), with a 35% decrease in can product label to include consideration of
transcriptional activity of UGT1A1 and lower lower initial dose requirement for individuals
enzyme activity than the wild-type (TA)6TAA who are homozygous for UGT1A1*28, although
allele (UGT1A1*1) [175]. Another UGT1A1 poly- the genetic testing is not a requirement. The pre-
morphism, UGT1A1*6 (rs4148323) carrying the dictive value of UGT1A1*28 polymorphism has
c.211G>A SNP and p.G71R substitution in exon recently been confirmed in a meta-analysis of 58
1, has also been associated with lower enzy- studies [180]. With the involvement of UGT1A1
matic activity [176]. Although the *28 variant in bilirubin glucuronidation confirmed by three
is more common in Caucasians (29%–40%) and meta-analyses [181–183] and the prevalence of
Africans (36%–43%) than in Asians (13%–16%), UGT1A1*6 among Asian populations, UGT1A1
the *6 is found only in Asians with a frequency may play a role in the high incidence of neonatal
of 16%–23%. hyperbilirubinemia in those populations [184].
UGT contributes about 35% of phase II drug A different UGT enzyme, UGT2B7, plays
metabolism and is involved in glucuronidation an important role in mediating the conversion
of endogenous compounds and xenobiotics. For of morphine to the pharmacologically active
UGT1A1, the substrates include bilirubin, SN-38 metabolite, morphine-6-glucuronide. Darbari
(active and toxic metabolite of the anticancer et al. reported that homozygous and heterozy-
drug irinotecan), raltegravir (inhibitor of the gous carriers of the G variant for the -840 G>A
HIV integrase enzyme), clozapine, bazedoxifene SNP (rs7438135) had significant higher parent to
(an investigational selective estrogen receptor metabolite concentration ratio compared to indi-
modulator for prevention and treatment of post- viduals with the A/A genotype (P = .03) [185]. A
menopausal osteoporosis), and eltrombopag (a second UGT2B7 SNP (rs7439366, C802T) was
Polymorphisms in Non-CYP450 Drug-Metabolizing Enzymes 19
implicated for morphine toxicity in a patient cells) recommended by the FDA, and the thio-
with the T/T genotype that resulted in increased purine drugs are one of several medications that
morphine-6-glucuronide formation [186]. have clinical guidelines available through the
CPIC [188,189].
Thiopurine-S-methyltransferase
Dihydropyrimidine Dehydrogenase
Thiopurine-S-methyltransferase (TPMT) is
(DYPD)
encoded by the TPMT gene that has a nonsyn-
onymous SNP and resulting in reduced TPMT In addition to being the initial and rate-
enzymatic activity. Although more than 31 vari- limiting enzyme that catalyzes pyrimidines
ants of the TPMT gene have been identified, the such as uracil and thymine, dihydropyrimidine
five most studied one are TPMT*2 (rs1800462, dehydrogenase (DYPD), a minor phase I metab-
G238>C, reduced activity), TPMT*3A (a hap- olizing enzyme, also mediates the metabolism of
lotype consisting of the two nonsynonymous 5-fluorouracil (5-FU) and capecitabine. Genetic
SNPs, G460>A and A719>G, abolished activ- polymorphisms in the DPYD gene that encodes
ity), TPMT*3B (rs1800460, G460>A, reduced DYPD result in DYPD-deficiency phenotypes
activity) TPMT*3C (rs1142345, A719>G, reduced with an overall frequency in the general popula-
activity), and TPMT*4 (rs1800584, G626>A, very tion of about 3%–5%, which varies significantly
low activity). About 95% of intermediate or low among many ethnic groups [190].
TPMT activity in affected patients are associ- With more than 30 SNPs in DYPD, the most-
ated with TPMT*2, TPMT*3A, or TPMT*3C. relevant decreased functional variants associ-
Approximately 10% and 0.3% of the Caucasian ated with grade 3- and grade 4-toxicities in
population is heterozygous and homozygous, 5-FU-treated patients include c.1905+1G>A,
respectively, of these mutant alleles. also known in the literature as DYPD*2A or
TPMT mediates the inactivation of thiopurine DYPD:IVS14+1G>A (rs3918290); c.1679 T>G,
drugs, including thioguanine, 6-mercaptopu- also known as DYPD*13 (rs55886062, p.I560S);
rine, and its precursor, azathioprine. Compared c.2846A>T (rs67376798 p.D949V); and c.1129-
to patients who possess the wild-type alleles, 5923C>G (rs75017182) [191,192]. Other vari-
homozygotes or heterozygotes for the TPMT ants such as c.85T>C (DYPD*9A, rs1801265,
mutant alleles have much higher levels of the p.C29R) do not result in altered DYPD activ-
cytotoxic thiopurine nucleotides and are at ity [193]. Among the four functional SNPs, the
higher risk for developing serious hematologi- G>A mutation within intron 14 results in a pro-
cal toxicities during treatment with standard- tein with no catalytic activity and is found in
dosage regimens of the thiopurine drugs [187]. approximately 40%–50% of patients who have
As a result, patients with absent and low TPMT either a partial or complete DYPD deficiency.
activity can only tolerate 5 and 50% of the stan- Homozygous and heterozygous carriers of
dard 6-mercaptopurine regimen. the variant IVS14+1G>A allele have complete
The TPMT metabolism represents one of absence and 50%, respectively, of normal DYPD
the most-investigated drug metabolic path- activity, and significant, sometimes life-threat-
ways that demonstrates the clinical relevance of ening 5-FU-related toxicities [194]. However,
genetic polymorphism. Currently, TPMT is the the risk of severe toxicity is not necessarily
only drug-metabolizing enzyme with signifi- related to DYPD genotypes [195]. This may be
cant acceptance and widespread testing in clini- due to sensitivity of the DYPD genetic testing
cal practice, with genotyping or phenotyping being dependent on which DYPD variants are
(determination of TPMT activity in red blood included in specific test panels [193].
N-acetyltransferase Glutathione-S-transferase
Genetic polymorphism in acetylation The human glutathione-S-transferase (GST)
capacity was reported more than 50 yrs ago, family of cytosolic enzymes contains at least
when two distinct phenotypes of rapid acet- 17 genes divided into seven classes:α, μ, π, σ,
ylator (RA) and slow acetylator (SA) were θ, ζ, and ω. Of these, the most important genes
noted in patients enrolled in a clinical trial are GSTM1 of the μ class, GSTT1 of the θ class,
of the antituberculosis drug isoniazid [196]. GSTP1 of the π class, and GSTA1 of the α class.
Subsequently, the phenotype differences were Both deletion polymorphisms and SNPs exist for
associated with enzyme activities of two cyto- GST genes. Gene deletion results in the null vari-
solic enzymes N-acetyltransferase-1 (NAT1) ants, GSTM1*0 and GSTT1*0 and loss of GSTM1
and N-acetyltransferase-2 (NAT2), which are and GSTT1 enzyme function, respectively. Two
encoded by the NAT1 and NAT2 genes, respec- polymorphisms of the GSTP1 gene have been
tively. The NAT2 enzyme is primarily respon- described: rs947894 carrying the exon 5 c.A1404G
sible for acetylation of aromatic amines and SNP, and p.I105V substitution at codon 105, and
hydrazines. Polymorphism in NAT2 results rs1799811 carrying the exon 6 c.C2294T SNP and
in more than 10 NAT2 alleles, with NAT2*4 p.A114V substitution at codon 114. Four different
reported as the wild-type allele, and NAT2*5 haplotypes have been described for the popula-
(rs1801280) carrying the c.341T>C SNP that tion: GSTP1*A (105Ile-114Ala), GSTP1*B (105Val-
results in the p.I114T amino acid change, 114Ala), GSTP1*C (105Val-114Val), and GSTP1*D
NAT2*6 (rs1799930) with c.590G>A SNP and (105ILe-114Val) [199]. A point mutation in the pro-
p.R197Q substitution, as well as NAT2*7 moter of the GSTA1 gene results in lower pro-
(rs1799931) with c.857G>A SNP and corre- moter activity associated with the GSTA1*B allele.
sponding p.G286E substitution as the primary In contrast to deleted GST genotypes, the GSTP1
variant alleles [197]. These three variant alleles and GSTA1 polymorphisms result in genotypes
account for the majority of the SA phenotype. with low-activity enzymes.
The prevalence of SAs varies significantly in The frequency of occurrence of the two GST
different ethnic groups: 90% of Arab popula- null alleles varies significantly among dif-
tions, 40%–60% of Caucasians, and 5%–25% of ferent populations. Between 42% and 58%
East Asians. of Caucasians and 27%–41% of Africans are
Substrates for NAT include numerous aryl- reported to be lacking the GSTM1 gene. For the
amine- and hydrazine-containing drugs such as GSTT1 gene, the null-allele frequency ranges
sulfamethoxazole, hydralazine, isoniazid, and from 2% to 42% for Caucasians, 50%–60% in
procainamide. High blood levels of these and Asians, 15%–20% of African Americans, and
similarly, acetylated drugs in SAs have been less than 10% in Hispanics [200,201]. The GSTP1
associated with lupus-like syndrome (hydrala- and GSTA1 polymorphisms have been reported
zine and procainamide), peripheral neuropathy to occur in up to 40% of Caucasians and 54%
(isoniazid), and liver damage (sulfapyridine). of Africans, and 40% of Caucasians and 41% of
In addition, to drug therapy, NAT2 polymor- Africans, respectively.
phism has also been implicated in susceptibil- GSTs are detoxification enzymes that medi-
ity to developing different types of cancer, with ate the conjugation of reduced glutathione with
SA having an increased risk after prolonged different substrates that include carcinogens
exposure to carcinogenic arylamines and other and chemotherapeutic agents, such as oxali-
industrial chemicals [198]. platin-based chemotherapy and chlorambucil
Polymorphisms in Drug-Transporter Genes 21
[200,202–204], with poorer response and reduced transporters, the better-known examples are
overall survival in patients with GSTM1*0 or ABCB1 (P-glycoprotein [Pgp] or MDR1), ABCC1
GSTT1*0 genotypes, and treated with oxaliplatin- (multidrug resistance 1 [MRP1]), ABBC2 (mul-
based chemotherapy or anthracycline-based tidrug resistance [MRP2]), and ABCG2 (breast
induction therapy [204–207]. Because GSTs are cancer resistance protein [BCRP]). For the SLC
detoxification enzymes, the shortened survival family, there are 360 members that are subdi-
in patients with reduced GST activity might be vided into 46 subfamilies. The better-known
related to severe drug-related toxicity, as evi- SLC transporters are organic anion-transporting
denced by a higher frequency of grade 4 neutro- polypeptide (OATP), organic cation trans-
penia in homozygous carriers of GSTM1*0 and porter (OCT), and organic anion transporter
treated with oxaliplatin-based chemotherapy (OAT). Genetic variants of the genes encoding
for their metastatic colorectal cancer [208]. The these drug-transport proteins (http://www.
important detoxification role of GST has also pharmGKB.org) have been discovered that
been reported in a recent study in which pedi- affect their expression, substrate specificity,
atric patients with GSTMI and CYP2C9 variants and/or intrinsic transport activity, and ulti-
have a higher risk of developing hemorrhagic mately disposition, efficacy, and safety of many
cystitis when treated with the combined regi- drug substrates.
men of busulfan and cyclophosphamide [209].
The ABC-Efflux Transporters
POLYMORPHISMS IN DRUG- ABCB1
TRANSPORTER GENES ABCB1 was the first recognized and the
most-studied ABC transporter. It is encoded
Membrane transporters are present at many by the highly polymorphic ABCB1, with more
endothelial and epithelial barriers, including the than 50 SNPs and three insertion/deletion poly-
blood brain barrier (BBB), the intestinal epithelial morphisms reported. The most common stud-
cells, the hepatocytes, and the renal tubular cells. ied SNPs are the c.C1236T (rs1128503) silent
By facilitating drug excretion into the gastroin- polymorphism in exon 12, the c.G2677A/T
testinal tract and bile, from the liver and kidney, (rs2032582) polymorphism in exon 21, and the
as well as limiting the amount of drug cross- c.C3435T (rs1045642) silent polymorphism in
ing the BBB, they provide an important physi- exon 26. The c.G2677A/T polymorphism results
ological role of protecting humans against toxic in a change in amino acid sequence p.A893S
xenobiotics, and have recently been recognized (G2677T) SNP or p. A893T (G2677A) SNP. Ethnic
as important determinants of drug disposition variations in allelic variant distribution are well
and response [210]. These drug transporters can known [211,212]. In addition, strong LD among
be broadly classified into two groups: the efflux these SNPs had been reported to create haplo-
adenosine triphosphate-binding cassette (ABC, types consisting of 1236C>T, 2677G>A/T, and
and formerly known as multidrug resistance 3435C>T. The three ABCB1 SNPs and their hap-
[MDR]) family of transporters, and the uptake lotypes (Table 1.3) are important in expression
solute carrier (SLC) family of transporters. In and function of ABCB1.
all, 49 members are present within the human The functional and clinical implication of the
ABC-transporter family. Based on homology ABCB1 polymorphism was first evaluated for
of their amino acid sequences, they are further the C3435T SNP with digoxin as the substrate,
classified into seven subfamilies. Of all the ABC demonstrating a relationship between lower
TABLE 1.3 Selected ABC Transporters Polymorphisms Indicating Allele Variants and Frequency,
and Drug Substrates
Allele Variants,
Genes Amino Acid Change Frequency (%) Drug Substrate Examples
ABCB1 C3435T 48%–59% in Caucasians Protease inhibitors (ritonavir, saquinavir, nelfinavir)

37%–66% in Asians Anticancer drugs (anthracyclines, taxanes, vinca
10%–27% in Africans alkaloids, imatinib)
Immunosuppressants (cyclosporine, tacrolimus)
C1236T 34%–42% in Caucasians Antibiotics (erythromycin, levofloxacin)
60%–72% in Asians Calcium channel blockers (diltiazem, verapamil)
15%–21% in Africans Digoxin, pivastatin, simvastatin
G2677T, A893S 38%–47% in Caucasians
32%–62% in Asians
≤15% in Africans
G2677A, A893T 1%–10% in Caucasians

3%–22% in Asians
1236C>T/2677G> 23%–42% in Caucasians

T/3435C>T 28%–56% in Asians
haplotype 4.5%–8.7% in Africans
ABCC2 1249G>A, V417I 22%–26% in Caucasians Reverse transcriptase inhibitors (tenofovir),

13%–19% in Asians Anticancer drugs (anthracyclines, vinca alkaloids,
14% in Africans methotrexate, SN-38 glucuronide), pravastatin, rifampin
ABCG2 421C>A, Q141K 6%–14% in Caucasians Anticancer drugs (methotrexate, imatinib, gefitinib, SN-38,
15%–36% in Asians SN-38 glucuronide, topotecan),
0%–5% in Africans Apixaban, atorvastatin, rosuvastatin, glyburide,
dolutegravir
expression of ABCB1 and increased digoxin [216]. Therefore, ABCB1 genotyping may have a
bioavailability and plasma concentration after role in predicting responses to protease inhibi-
oral administration in TT homozygotes with tors. The ABCB1 haplotype TTT (rs1128503,
reduced ABCB1 activity [213]. In two separate rs2032582, rs1045642) was reported to be respon-
studies, investigators showed that CC genotype sible for increased morphine exposure and the
of the C3435T SNP (increased Pgp expression) exhibition of morphine sensitivity in a patient
is associated with reduced efficacy and a higher [186]. In addition, Sadhasivam et al. reported
risk of myalgia after treatment with atorvastatin an association between another ABCB1 variant
[214] and increased statin-associated increase (rs9282564) and increased risk of morphine-
in serum creatine kinase [215], presumably due induced respiratory depression in patients with
to lower intracellular concentration and higher the GG and GA genotypes of this SNP [217].
plasma concentration of statin. Nevertheless, conflicting results have been
The polymorphism also affects plasma con- reported regarding the functional and clini-
centrations and clinical effects of protease cal significance of the polymorphism for dif-
inhibitors. After 6-mo therapy with efavirenz or ferent substrates including psychotropics (see
nelfinavir, patients with the TT genotype had a Chapter 7), antiretroviral protease inhibitors,
greater rise in cluster of differentiation 4 (CD4) immunosuppressants, and anticancer drugs.
cell counts than patients with the CC genotype This may be due to the use of different assays
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Gastric Vertigo.—Trousseau certainly misled the profession as to the
frequency of this form, but he did little more than represent popular
medical views, and we may now feel sure that a good many so-
called gastric vertigoes are due to lithæmia or to troubles of ear or
eye. There are, I think, three ways in which the gastro-duodenal
organs are related to the production of vertigo. Acute gastric vertigo
arises in some persons inevitably whenever they eat certain articles,
and the limitations are odd enough. Thus, I know a gentleman who
cannot eat a mouthful of ice-cream without terrible vertigo, but
otherwise his digestion is perfect. I know another in whom oysters
are productive of vertigo within ten minutes; and a curious list might
be added, including, to my knowledge, milk, eggs, oysters, crabs,
etc. In these cases digestion is arrested and intense vertigo ensues,
and by and by there is emesis and gradual relief.
In other cases, owing to over-feeding or any of the numerous causes

of acute dyspepsia, an individual has a sudden attack of acid
stomach, and as this gets to its worst he has alarming vertigo. In
these cases the room whirls around or the pavement rocks; the
balancing power is disturbed or lost; the sense of movement in the
brain itself is sometimes felt; there are slight buzzing or humming
sounds in one or both ears; there may be double vision, which
comes and goes, while the power to think is lessened and the terror
created is quite unendurable. At last come the sweat of nausea,
emesis, and relief, with a gradual fading away of all the symptoms.
As a rule, such an attack need cause no uneasiness as to a fatal

result, but, unless the case be handled with skill, it is apt to repeat
itself with or without repetitions of the originating cause, until what I
have called the status vertiginosus is created, and we have more or
less steadily present a slight sense of defective balance, of
confusion of mind, of blurred vision, and, more rarely, of slight noises
in the ears. After two or three grave attacks, attacks are added for
which the patient sees no cause. He lives in a state of constant
terror, and the status vertiginosus attains its highest development,
and may last for unlimited periods, while the brain becomes
endowed with new morbid susceptibilities. To read, to write, to face
sudden sunlight, to see moving bodies or passing crowds, cause
vertigo. Loud sounds disturb the balance; even music will affect it.
Emotions or any decided mental efforts are equally competent to
bring on attacks, while fatigue or sudden changes of posture have to
be alike avoided.
I have sketched an extreme case, but whatever causes grave vertigo

is able to bring on the set of symptoms here described, which are,
after all, more apt to be due to aural than gastric states.
Vertigo as a result of chronic dyspepsia in any of its forms is rare,

and as a rule is less severe than that which grows out of acute
gastric dyspepsia. The sensory symptoms are trifling, and the
confusion of head and the lack of balance less notable, while the
vertigo, which is more or less constant, seems to be most often met
with two to four hours after meal-time, so that it is usually doubtful as
to how much is due to reflected impressions from the digestive
tracts, and how much to the direct influence of imperfect material in
the circulation.
In a third form the gastro-intestinal tract is but indirectly concerned.

In a person who is anæmic, or who is nervous and perhaps
hysterical without being anæmic, but in whom it is impossible to
detect in the stomach or bowels, in the feces or urine, any sign of
defective digestion or of malassimilation, we find that during the act
of digestion there is at some time, and in a few cases constantly,
some transient but not grave vertigo.
This is due simply to the influence exerted on an over-sensitive head

of a normal functional activity, which may act directly as any
peripheral cause would act, or may be due, in the anæmic, with this
to the withdrawing of blood from other parts of the body which occurs
in digestion. It is an illustration of what is too often overlooked, the
capacity of a healthy functional act to disturb morbidly a sensitive
brain.
Aural Vertigo.—Vertigo may be due to a variety of irritative causes

acting on the outer, middle, or inner ear. We shall consider them
separately.
Vertigo from Causes acting on the External Ear.—In animals I have

found that the injection of iced water or a rhigolene jet into the
meatus is at once the cause of convulsive movements in the rabbit,
and that repetitions of this cause at last a permanently vertiginous
state, so that when a rabbit or guinea-pig thus disordered was shut
up in darkness for some hours, sudden sunlight caused it to be for a
few moments vertiginous. It is remarkable that while in birds many
parts of the skin are competent under irritations (Weir Mitchell, Ott,
Brown-Séquard) to give rise to vertiginous phenomena, in mammals
only the skin of the external auditory meatus appears to be thus
responsive. The author was himself the best illustration of this fact.
Some years ago, when by mishap water at about 52° F. was thrown
into his left ear, he fell instantly on his left side, with slight
disturbance of vision, the room seeming to rock in the direction of the
fall—that is, to the left. He arose with some difficulty, his head
swimming, and with a distinct sense of lack of power in the whole left
side, and with, for a half hour at least, an alarming tendency to
stagger to the left.
Thus, injections of cool water in some cases (or in others of water at

any temperature), and in certain persons very hot water, will cause
vertigo. Foreign bodies—hardened wax, aspergillus, ulcers—or any
inflammation may occasion it, while it is curious that usually the
painful abscesses of the ear do not, especially in children, who are,
as a rule, less liable to vertigo than are adults.
The tendency of aurists is, I believe, to explain the phenomena by

either direct influence propagated as sound-waves through the
auditory apparatus to the labyrinth, or by admitting inhibitory
impressions affecting the vaso-motor loops and causing increased
pressure in the semicircular canals. I am disposed to think that the
effect may be a more direct one, and to regard the centres as
directly influenced through the fifth nerve, including vaso-motor
phenomena of course—a question to be, however, easily solved in
the laboratory.
In this form of vertigo tinnitus is slight or transient, coming and going,
or if permanent but faintly felt.
Middle-ear vertigo may arise from any inflammation of the part or

from closure of the Eustachian canal. There are then direct
mechanical influences affecting the labyrinth, as well as sensory
irritations, not causing auditory phenomena; whilst also the inner ear
is apt soon to suffer from direct propagation of inflammatory
processes. There is then paroxysmal vertigo, variable hearing,4 and
early tinnitus.
4 Burnett, Sect. Otol., Int. Med. Cong. Proc., 1876.
Inner-ear vertigo seems to be due to irritations, auditory, mechanical,

or inflammatory—whatever disturbs seriously the nerves of the
semicircular canals, since, if we may trust recent research,5 the
cochlea is not a source of vertiginous impressions. This form of
vertigo was first described with pathological proof by Menière in
1860, and is probably in its variety of degrees the most common of
all the origins of dizziness.
5 Gellé.
The acute attack is nearly always preceded by more or less

deafness, and in many cases by middle-ear catarrh,6 with or without
tinnitus. More rarely all the symptoms arise abruptly. There are
sudden tinnitus, deafness, nausea, vertigo. The loss of hearing
remains, and is variable, or, finally, the hearing is lost altogether. The
tinnitus is permanent or varies in amount, but as the deafness grows
complete the vertigo disappears, and although cases of death have
been described, labyrinthine vertigo is, as a rule, prone to get well in
time.
6 Burnett.
Single attacks are rare. It is apt to repeat itself, and finally to cause
all the distressing cerebral symptoms which characterize the worst
gastric vertigo, and at last to be capable of easy reproduction by
light, heat, over-exertion, and use of the mind or eyes, by emotion, or
by gastric disorder.
Even after the vertigo has ceased to exist the fear of loss of balance
remains, while perhaps for years the sense of confusion during
mental effort continues, and gives to the sufferer a feeling of what a
patient described to me as mental vertigo—some feeling of
confusion, lack of power to concentrate attention, loss of hold on
trains of thought, with now and then a sensation as if the contents of
the cranium moved up or down or swayed to and fro.
The attack in the gravest forms is often abrupt, and, according to

Charcot, is always preceded by a sudden loud noise in the affected
ear. I have, however, notes of many cases in which this was not
present. The patient reels, staggers, or falls, usually forward or to
one side, loss of consciousness being very rare. The sensory
hallucinations are remarkable. If at rest or after his fall he seems to
himself to sway, and tends to pitch or roll over; the bed rocks, the
room and its contents reel. The patient's terror is intense; he
clutches the bed; seeks relief in fixing his eyes on an object, which in
slight attacks is competent to relieve, or else he closes them. The
least motion starts the vertigo afresh. In some cases turning the
head or looking up will bring it back, or the patient may remain for
days or weeks in this condition, with continuous dizziness and
frequent recurrences of severe vertigo, while there is more or less
constant nausea and sometimes vomiting.
There should be no trouble in distinguishing the cases in which

deafness exists, but the nausea is apt to direct attention to the
stomach. Tinnitus is common in vertigo, however arising; and when,
as I am sure does chance, there is for years now and then a slight
and transient deafness with vertigo, or a permanent deafness in one
ear, and therefore not noticed, the inner ear is apt to be overlooked
as a source of trouble.
Vertigo from growths on the auditory nerve before it enters the inner
ear is rare in my experience. It is described as slow in its progress,
the deafness and tinnitus being at first slight, but increasing steadily,
while there is tendency to fall toward the side affected.7 In the cases
of disease attacking the seventh nerve within the cranium there is
usually so much involvement of other and important nerve-tissues as
makes the disorder of audition and equilibration comparatively
unimportant.
7 Burnett.
Vertigo from coarse organic lesion of brain, such as a tumor, is

common, and is, indeed, rarely absent in such cases. The cases in
which it is lacking or least remarkable are, I think, to be found in the
anterior and middle cerebral lobes, while it is almost sure to exist at
some time when the tumor is in or near the cerebellum.
Growths or other causes of irritation in the crura of the cerebrum or

cerebellum, or on the pons, are sure to give rise to disturbed
equipoise or to methodical involuntary actions; but these are not
always, though often, accompanied with delusive impressions as to
exterior objects, or with the other symptoms found in typical vertigo. I
recall one remarkable case where a blow on the left side of the
occiput resulted in a tendency to roll to the left which finally
triumphed over volitional control, so that the patient would at times
roll over on the floor until arrested by a wall. After the rotation had
lasted for a minute there was, when it ceased, a false sense of
movement of objects to the left, but at the outset there were no
sensory illusions, and at no time any mental disorder. The patient
recovered, and is now in good health; but it is interesting to learn that
while, during the time of these attacks, he had normal hearing, he
has gradually lost hearing in the left ear and acquired permanent
tinnitus. I have reached the conclusion that there is a group of
functional vertigoes, and that in some of them the trouble lies in the
semicircular canals; that is to say, the lesion is slight or transient, but
in rare cases recurs until a more distinct and permanent result
justifies the original diagnosis.
OCULAR CAUSES OF VERTIGO.—For the most part, the eyes as a

source of vertiginous impressions are neglected in the textbooks; but
as the cause of certain of the slighter vertigoes, and as a fertile
agent in emphasizing or recalling vertigoes due to the stomach or
inner ear, they are well worthy of careful study, nor is it ever wise to
neglect these organs in cases either of headache or of vertigo.
A number of eye conditions cause giddiness or increase it or

reproduce it. Thus, sudden loss of accommodation in one eye or in
both may occasion it, and perhaps the enlarged pupil may have its
share, since even in healthy people, and surely in all habitually
vertiginous patients, sudden exposure to brilliant light gives rise to
sense of instability.
Abrupt change in intraocular pressure is another cause, as in acute

glaucoma or in sudden partial collapse of the eye from discharge of
the aqueous humor.
Permanent vertigo of quite severe character may arise from

astigmatic defects, and from almost any form of disorder affecting
steadily the power of the eye to accommodate itself to distances; but
simple myopia of moderate grades, excessive one-sided myopia, or
presbyopia is unlikely to do so. Oculo-motor troubles, paralytic or
spastic, are very effective causes of vertigo, which is sometimes
quite promptly producible by the wearing of a prism on one eye or by
the use of glasses which over-correct, or if exact are for some
reason badly borne. This latter is apt to be the case, I think, in
accurate corrections of long-standing hypermetropic astigmatisms.
There is one point on which, in this connection, I have again and
again insisted: Optically defective eyes may exist through life without
notable brain disturbance, unless, from over-use with worry, work
under pressure, the strain of prolonged or of brief and intense
emotion, or any cause of ill-health, the centres become sensitive, as
they are then apt to do. When this occurs defective eyes, and in fact
many other sources of irritation, grow at once into competence for
mischief, and occasion vertigo or headache or other cerebral
disorders.
Then it is that even slight defects of the eye may cause vertigo,
which if usually slight and transient, coming and going as the eyes
are used or rested, is sometimes severe and incapacitating. I have
over and over seen vertigo with or without occipital pain or distress in
persons whose eyes were supposed to be sufficiently corrected with
glasses, but who found instant relief when a more exact correction
was made; and this is, I think, a matter which has not yet generally
received from oculists the attention it demands.
When vertigo, essential, gastric, or aural, is present, the use of the

normal eye becomes a common source of trouble. Bright lights,
things in irregular motion, reading or writing, and especially rapid
changes in accommodation, as watching the retreat or approach of a
moving object, are prone to cause or increase the dizziness.
Vertigo in old age, if not due to the stomach or defective states of the
portal system, kidneys, or heart, is either caused by atheromatous
vessels or multiple minute aneurismal dilatations of vessels, or in
full-blooded people by some excess of blood or some quality of
blood which is readily changed by an alteration in the diet, of which I
shall presently speak. Whatever be its source, it is in the old a matter
of reasonable anxiety.
Laryngeal Vertigo.—Under this name J. R. Gasquet,8 and later M.

Charcot, have described a form of vertiginous attack in which
irritation of the larynx and a spasmodic cough invariably precede the
onset. I have never seen such cases, nor do they seem to me
entitled to be called vertigo. The symptoms are these: After
bronchitis, gout, or rheumatism there occurs an irritation of the larynx
or trachea, or of both, which at times is expressed in the form of a
tickling cough, simple or in spasms. With these arises a slight sense
of vertigo, or else in the grave attacks the patient falls insensible,
without convulsion or with no more than one may see at times in
fainting. The face is flushed, even deeply, and the attacks last but a
few moments. The term vertigo seems to have in such a group of
symptoms but little application, nor do these attacks ever bring upon
the sufferer the status vertiginosus.
8 Practitioner, Aug., 1878.
Vertigo in Anæmia and in Neurasthenia and Hysteria.—A passing
vertigo readily caused by abrupt changes of posture, felt even in
health, at times is far more profoundly experienced in grave anæmic
states, while in neurasthenic conditions, with deficiency of globules
or defect of hæmaglobin, it is still more common. In well-pronounced
neurasthenic states, where there is no measurable lack of red
corpuscles, but where hæmaglobin is apt to be deficient, it is a
frequent symptom, and is then either an immediate result of
functional central disorder or of gastric or optical troubles. While the
dizziness of neurasthenia is never profound, certainly never repeats
the agony of Menière's vertigo, it is apt to be but a too constant
symptom, and to be, like the other disqualifying cerebral symptoms
of neurasthenia, almost the last to get well. Usually there is little,
often no, tinnitus, no deafness, no nausea, slight but a pretty
constant sense of unsteadiness, and rarely or but for a few moments
any false subjective visual illusions. This, at least, is the type, but, on
the other hand, in extreme cases and within these limits the brain is
liable to be confused, and the sense of need for difficult controlling
volitions called out by almost any use of the eyes in near vision,
owing usually to oculo-muscular paresis. Even looking at a mirror or
at persons passing by, or the least distinct mental effort, may
reproduce it. There is, too, in most of these cases an extreme sense
of mental confusion, and more often a false sense of movement
within the head than without, while in no other patients is the sexual
act so apt to increase all of the symptoms in question.
Hysteria, as might be expected, offers now and then examples of

vertigo. It does not exclude the presence of true aural, optic, or
gastric dizziness, which is then apt to become the starting-point of a
long train of hysterical disorders. On the other hand, we meet with
hysterical vertigoes which, in a sense, may be said to simulate any
of the more usual types. I have certainly seen hysterical girls with
deafness, tinnitus, and a great development of equilibrial
disturbance, in whom the disease passed away without leaving a
trace behind it, so that in these cases some caution is needed as to
prognosis. They become far more difficult to deal with when they are
found in old women or women in advanced middle life, since it is
then hard to know what share senile changes may have in the
production of the symptoms.
Vertigo from mechanical causes, such as sea-sickness, railway

sickness, swinging, etc., it is hardly worth while to deal with here at
length. The research of Prof. James has made it probable that
disturbances of the labyrinth are responsible for the vertigo of sea-
sickness. Certainly, deaf-mutes seem to have lost the power to be
made vertiginous from rotation, and do not suffer at sea.
It is, however, worth recording here that I have more than once seen
enduring vertiginous status, with occasional grave fits of vertigo,
arise out of very prolonged sea-sickness. In the last example of this
sequence seen by me there was, after a year or more, some
deafness.
The elevators in use in our hotels sometimes cause, in those who

live in them all day and control their movements, a cumulative
vertigo, and I have known such persons to be forced on this account
to seek other occupation.
Essential Vertigo.9—There can, I think, be no doubt that the centres

may evolve the symptom vertigo from causes which are transient,
and the nature of which sometimes evades our most careful search.
We reach the diagnosis of a state of essential or true central vertigo
by exclusion, but, once developed, this vertigo does not greatly differ
from vertigo of peripheral cause. It is sometimes associated with
states of pallor, at others with flushing, while the disturbance of
balance and the false perceptions as to the place of outside objects
may vary from the least to the most profound disturbance. In some of
these examples the nausea or emesis does not appear at all, and
the patient, escaping acute attacks altogether, may with occasional
aggravation continue to be merely and almost constantly vertiginous.
9 Ramskill and others.
The TREATMENT of acute attacks of vertigo, however caused, consists,

of course, in rest in bed and in the use of large doses of bromides or
hydrobromic acid, and if the trouble be grave in that of hypodermatic
injection of morphia, and where there is plainly pallor of face in
inhalations of amyl nitrite or in the exhibition internally of nitro-
glycerin and alcoholic stimulants. Sometimes to lie on the floor in
total darkness is helpful when the disorder continues and is severe. I
have known patients liable to be attacked suddenly to carry a little
flask of brandy, and to find that very often an ounce of brandy, taken
at the first sign of trouble, would enable them, by also lying down, to
break the attack; and ether is yet more efficient. After the severer
sense of vertigo has gone they find that stimulus is comforting, and
for a time at least gives strength. I have used amyl nitrite but twice.
In each case it is said to have broken the attack, but I have had no
larger experience with it.
Gastric vertigo demands, in the acute attacks, a treatment directed

to the cause. Antacids may be valuable, or in arrested digestion
emetics, but in all cases these should be followed for some weeks by
moderate doses of bromides, while gouty or lithæmic states should
be treated by the usual means.
Vertigoes from portal disturbances are best treated by aperients, and

a like lessening of animal food, which, in the vertigo of old age or
middle life arising from excess of blood, will also be found available.
The change of cerebral states of passive congestion, which can be
brought about by a pure vegetable or milk-and-vegetable diet is
sometimes quite remarkable; and I know of few things in
therapeutics which are more satisfactory.
The treatment of anæmic or neurasthenic vertigo involves nothing

peculiar. So long as the want of blood lasts, or some one of the
several groups of symptoms loosely classed as neurasthenia exists,
so long will the associated vertigo endure.
Aural vertigoes are easy or difficult to treat, as they arise from

external or middle and internal ear troubles. Irritations in the external
ear are of course to be removed, and catarrh of the middle ear to be
treated by attention to its conditions, whether of blocking of the
Eustachian canals with depression of the membrana tympani or of
accumulations in the middle ear, with the opposite state of fulness.
Aural vertigo, as has been pointed out, may arise from disorders of
any part of the ear, so that it is needful to look for wax, ulcers, foreign
bodies, etc. in the external meatus; for catarrhal states, closure of
the tubes of Eustachius, states of fulness or of vacuum in the middle
ear; and for inflammatory conditions, direct or transmitted, in the
inner ear. Very often vertigoes from irritations of the outer or middle
ear may be relieved with more or less ease, but labyrinthine vertigo,
however acquired, is always troublesome, often lasting, and if grave
gets well only when deafness has become great.
In this form of vertigo, and while acute, morphia is very serviceable,

and is to be used with full doses of bromides. When, as happens,
both cease to be of value, Charcot's plan of the heroic use of quinia
salts I have seen do good; but it is advisable to use with it
hydrobromic acid in full doses. It has been constantly my practice to
employ over the mastoid or on the neck frequent but not deep
cauterization. It is well in these cases to warn some near relative that
while remote relief from the vertigo is probable, it will be bought at
the cost of increasing deafness, and that we can rarely do more than
help the patient to endure his state until time and the slow processes
of pathological change have come to our aid.
Optic vertigo, if essentially that, is rarely discovered without the help

of some one trained to study the defects of vision. Its relief demands,
of course, as a rule, glasses, or in extra-optical muscle-troubles
these or a compensatory operation. When, however, the vertigo has
been grave, it is needful to manage corrections of the eyes with care
and judgment, and sometimes experimentally. The sensorium,
having become over-excitable, does not always bear accurate
correction of the eyes, or this increases the vertigo. Then the glasses
are cast aside and the case progresses. In others—and this is purely
a matter of individual experimentation—nothing will answer except
the most careful and absolute corrections: anything less does no
good.
These remarks apply with equal force in chronic vertigoes, essential,
gastric, or other. Defective eyes, unfelt in health, soon begin to
trouble a head sensitized by chronic dizziness, and optical defects
which are sometimes but trifling become then competent to increase
the growing intracranial disorders, or to assist lithæmia or a
troublesome stomach to create and sustain vertigo.
The Status Vertiginosus.—I have tried to make clear elsewhere and

in this article that in several forms of vertigo the disorder ceases to
owe its onsets to extracentral irritations, and becomes essential,
precisely as happens in some epilepsies, and that we then are apt to
have, with more or less distinct attacks or with no attacks, long
continuance of a group of symptoms which constitute the status
vertiginosus. Its treatment is important, because of its alarming and
disqualifying effects. The attacks are often the least part of it, while
the lack of power to read and write, to go into crowded streets, to
face light, or to exercise, or stand emotions or the slightest mental
strain, surround its management with embarrassments, and are well
fitted to end in melancholia or hypochondriasis.
In these cases, after the eye has been corrected, the diet should be
regulated with care. In extreme cases it may become desirable to
limit it to milk, fruit, and vegetables where no obvious peculiarities
forbid such a regimen; and I have found it useful to insist also on
some food being used between meals.
I like, also, that these patients rest an hour supine after each meal,
and spend much time out of doors, disregarding their tendency to lie
down. Exercise ought to be taken systematically, and if the vertigo
still forbids it, massage is a good substitute. At first near use of the
eyes is to be avoided, and when the patient resumes their use he
should do this also by system, adding a minute each day until
attainment of the limit of easy use enjoins a pause at that amount of
reading for a time.
Now, as in vertigo, especially labyrinthine, the eyes become doubly

valuable as guiding helps to correct equilibration, I have long found it
useful to train these patients to stand and walk with them closed. At
first this is as difficult, or may be as difficult, as in locomotor ataxia,
but the practice is sure to add steadiness to the postures. Somewhat
later I ask my patient deliberately to make such movements of the
head and such efforts of mind or memory as are apt to cause vertigo
or confusion of head, and to conquer or inhibit these consequences
by a prearranged effort of will; and these means also I have found
useful. Meanwhile, nothing usually in these cases forbids the use of
tonics or of moderate doses of bromides. As I have said, change of
air is very serviceable. It is indeed rare that cases do not yield to
some such combination of means, but very often it will happen that
the fears of the patient are his most grievous foes, and are to be
dealt with after every real symptom has vanished.
TREMOR.
BY WHARTON SINKLER, M.D.
Tremor is a prominent symptom of many diseases of the nervous

system, and is met with as an effect of certain poisons which have
been taken into the system; so it should not be considered as a
disease in itself. It may, however, occur without being associated
with any other abnormal condition which can be discovered. It is then
called tremor simplex or tremor essentialis. The tremor of old age
(tremor senilis) comes under this head.
Tremor is sometimes hereditary, and may exist from early life. I have
a patient in whom there is a trembling of the hands which has lasted
since childhood. This lady's mother and grandmother both had the
same form of tremor, and one of her own daughters also has it. In
this case the trembling is most marked when voluntary movements
are attempted, but it does not materially interfere with writing,
sewing, or any other act she wishes to accomplish. There is slight
tremor when the hands are at rest.
Tremor simplex is seen in hysteria. In this disease it affects the

hands and the facial muscles as well. It is not uncommon in these
cases to find the tongue tremble excessively when protruded.
Tremor from chronic poisoning is usually from the absorption of lead,

mercury, or some of the narcotic drugs or alcohol. Lead tremor is to
be looked for among persons who are exposed to the action of lead,
such as painters, printers, or manufacturers of white lead.1 Such
persons generally have had some other symptom of lead-poisoning,
such as colic or paralysis. The tremor, however, may be the only
symptom of saturnine poisoning. Mercurial tremor is not so often
seen. It occurs in looking-glass makers or those who work in
quicksilver, and may also be a result of the medicinal administration
of mercury. The tremor from the excessive use of alcohol or opium is
familiar to all. Tobacco, if used immoderately, also causes trembling
in the hands. Tea or coffee may have the same effect. There are
other drugs which, when taken for a length of time, are liable to
cause tremor. Quinine is one of these.
1 Lead in hair dyes or in cosmetic powders often gives rise to plumbism by its
absorption by the skin.
Exhausting diseases, like the fevers, or any conditions which

enfeeble the system, cause tremor which occurs in voluntary effect. I
saw a lady some years ago who was greatly weakened by a
malignant growth. She was extremely anxious to sign her name to a
legal paper, but, although the hand was perfectly quiet when at rest,
when she attempted to write the first letter such intense tremor came
on that it was impossible for her to make any mark which was
legible.
Tremor follows violent bodily exertion or mental excitement. The

action of cold or the chill of intermittent fever is accompanied with an
extreme degree of trembling, which we all know. Tremor is also a
result of neuritis, but in this case it is associated with other
symptoms.
SYMPTOMS.—Tremor is met with as a fine or a coarse trembling. We

may also find a fibrillar tremor, such as exists in progressive
muscular atrophy. Tremor is divided by some (Van Swieten, Charcot,
and others) into two classes: the first is where the tremor occurs
while the part is at rest; the second is where it comes on during
volitional muscular movements. The former has been termed by Van
Swieten tremor coactus, because he believed that it arose from an
irritation which affected the nervous centres in an intermittent way.
The latter he conceived to depend upon a defect of stimulus, the
result of an insufficient amount of nervous fluid, which causes
contraction of the muscles under the influence of the will. This he
called tremor a debilitate.2
2 Charcot, Lectures on Diseases of the Nervous System.
In paralysis agitans we have an example of tremor coactus, and in

disseminated sclerosis, where the tremor occurs only as muscular
effect, it belongs to the variety of tremor a debilitate. Those divisions,
however, are of but little importance.
When tremor first begins it is slight in degree and extent, and occurs
generally only on voluntary effort. Later there may be a constant
trembling even when the part is at rest. Beginning usually in the
hands, it may extend to the head and legs. It is seen in the tongue
and facial muscles after the disease has lasted for some time.
In some cases the trembling can be controlled to some extent by a
strong effort of will. The tremor from alcohol or opium is most marked
when the individual has been without the use of the stimulant for a
short time, and the trembling may be temporarily checked by
renewing the dose of alcohol or opium as the case may be.
The muscular trembling from plumbism and mercurial poisoning is

more violent than the other forms of simple tremor, and often
resembles the tremor of paralysis agitans. In toxic tremors there are
often secondary paretic symptoms and indications of other
disturbances of the brain and nervous system.
In simple tremor there is no loss of muscular power, and the

electrical reactions of the affected muscles are not abnormal. The
duration of simple tremor is almost always great. Usually it persists
throughout life, becoming more general and more intense as the
subject of it grows older. The tremor of hysteria is shorter in duration.
Occasionally there are seen cases of simple tremor, which are
apparently the result of some trivial cause in a nervous person,
which last but a short time.
I have seen a case of tremor of the head in a woman of about forty

years, in which the trembling ceased entirely after it had lasted
several weeks. Hammond3 describes what he calls convulsive
tremor. Under this name he includes cases of non-rhythmical tremor
or clonic convulsions, which are unaccompanied by loss of
consciousness, but are paroxysmal in character. Pritchard in 1822
presented an account of this affection and related two cases;
Hammond mentions six cases. The affection is characterized by
paroxysms of violent and rapid convulsive movements, which are
more or less general and occur many times a day. The seizures last
from a few minutes to several hours.
3 Diseases of the Nervous System, p. 696.
The PROGNOSIS in convulsive tremor seems to be favorable.

Tremor may be regarded as a form of clonic spasm. It consists of
slight intermittent contractions of individual muscles or groups of
muscles. Fibrillar tremor, such as is seen in progressive muscular
atrophy, depends on contractions and relaxations of the muscular
fibrillæ, and can be seen under the skin, but does not cause any
movements of the limb.
There are no pathological data for explaining what portions of the

nervous system are the seat of disease in simple tremor. In
experiments upon the lower animals it has been found that trembling
occurs in muscles which have been separated from the nerve-
centres by division of the nerve. So too in man: when there has been
a wound or section of a nerve accidentally, there is likely to be
tremor in the muscles which it supplies.
The tremor does not begin at once on section of the nerve, but
comes on after a few days. As the peripheral end of the nerve
undergoes degeneration the tremor increases. It may last months or
even years.
In some of the conditions where tremor occurs the influence of the

will is weakened or is entirely absent. This is seen in hysterical
trembling and in the tremor of old age as well as in those cases
where there is general enfeeblement of the body, as in the fevers.
Trembling is connected with disease of the pyramidal tracts, because

in this way the influence of the cerebral centres is withheld from the
muscles. When a muscle is in a condition of tonic spasm, it is the
result of the running together of very rapidly-repeated muscular
contractions. It is like the contraction in a muscle from an interrupted
electrical current. If the interruptions are slow, the muscular
contractions are seen at intervals like a tremor; but if the
interruptions are rapid from frequent vibrations of the hammer of the
instrument, then the contractions in the muscle are fused together,
as it were, and the muscle is in a state of tonic spasm.
It is held by some writers that tremor is caused by the want of

balance between the cerebrum and cerebellum. When, for example,
the control of the cerebrum is enfeebled the action of the cerebellum
is so great as to bring about tremor by its uncontrolled power.
If we accept the first view, we must consider the tremor as a

preliminary stage of paralysis; for the lesion, which at first is slight
and causes only an interruption of the conduction of impulses from
the brain to the muscles, as it becomes more extensive totally
prevents conduction, and paralysis ensues.
Hughlings-Jackson's view, that general convulsions are the result of

discharges from the cortex of the brain, and that the tonic
contractions of tetanus are caused by discharges from the cortex of
the cerebellum, may be applied to the pathology of tremor as well.
When, for instance, in a disease like disseminated sclerosis a
voluntary effort instead of causing a steady muscular contraction
results in irregular spasmodic contractions and relaxations of the
muscle, we may imagine that a series of discharges were taking
place from the cortex of the cerebellum as long as the voluntary
efforts were persisted in. On the other hand, in paralysis agitans it is
more probable that a lack of conducting power in the pyramidal
tracts prevents the influence of the centres being continuously
exerted upon the muscles through their motor nerves.
It is probable that in simple tremor the lesion is situated in the spinal

cord; for in this disease we seldom see any evidences of cerebral
disturbance. There are no paralytic or psychical symptoms, and no
vertigo. In toxic tremors the disease is no doubt located in the brain,
for accompanying the trembling resulting from alcohol, opium,
mercury, and other drugs are mental changes and more or less
muscular enfeeblement.
TREATMENT.—Should the tremor depend upon some cause which can

be discovered, of course the obvious course is to attempt to remove
the source of trouble. The effort is of greater or less success in
different conditions. The tremor from mercurial poisoning sometimes
yields to treatment which is directed to the elimination of the
mercury. The free administration of the iodide of potassium is the
best means to be used, and is often successful. The same means
are available in lead tremor. Of course the patient must be removed
during treatment from the risk of further absorption of the poisonous
substances.
In simple tremor many remedies have been recommended, but the

results of treatment are not encouraging. Baths of various kinds and
galvanism have been used, and many drugs are advised.
Hyoscyamus and its alkaloid, hyoscyamine, have enjoyed a high
reputation, and good results have been reported from their use. I
have seen relief, but not cure, from their administration. Arsenic is a
more reliable remedy and it may be used hypodermically. Eulenburg4
has used this method with good results. I have given arsenic per
orem with beneficial effects in cases of simple tremor. In a case to
which I have referred above the tremor was relieved while the patient
was taking Fowler's solution, and on changing to hyoscyamus the
trembling got worse. On returning to the arsenic the symptoms
improved, and finally the tremor ceased after the remedy had been
taken for some weeks. Hysterical tremor requires that the hysteria
should be relieved. Franklinic electricity sometimes controls the
tremor in these cases.
4 Ziemssen's Cyclopædia, vol. xiv. p. 392.
PARALYSIS AGITANS.
BY WHARTON SINKLER, M.D.

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Dr. Scott dedicates this book to Gillian, Camille, and Harvey.

Scott R. Penzak Department of Pharmacotherapy, Toshiyuki Someya Department of Psychiatry,

Pharmacogenomics and pharmacogenetics book. In addition, we have included two chap-

Objectives2 Polymorphisms in Drug-Transporter Genes 21

Pharmacogenomics, Second Edition

OBJECTIVES The human genome comprises approxi-

Active: Normal activity Extensive metabolizers:

in Asians (about 0%–1% of population) and is converted by CYP2D6 to the pharmacologically

Codeine CYP2D6*1 ×3 Life-threatening opioid intoxication exacerbated by drug [25]

CYP2D6*2A/*2×2 Fatality in a breast-fed baby whose mother is a UM [26]

CYP2D6*1 ×N Fatality in a two-yr-old child due to respiratory arrest [27]

Hydrocodone CYP2D6*2A/*41 Fatality in a child who also received concurrent [33]

Oxycodone CYP2D6 UMs Greater toxicity, especially in those administered [32]

CYP2D6 gene duplication Tramadol-related respiratory depression [35]

response and CYP2D6 genotype in Japanese metabolically as PM during concurrent adminis-

dose-dependent manner in which carriers of two effectiveness of pharmacogenomics-guided dos-

POLYMORPHISMS IN NON-CYP450 thrombopoietin receptor agonist for the man-

ABCB1 C3435T 48%–59% in Caucasians Protease inhibitors (ritonavir, saquinavir, nelfinavir)

G2677A, A893T 1%–10% in Caucasians

1236C>T/2677G> 23%–42% in Caucasians

ABCC2 1249G>A, V417I 22%–26% in Caucasians Reverse transcriptase inhibitors (tenofovir),

In other cases, owing to over-feeding or any of the numerous causes

As a rule, such an attack need cause no uneasiness as to a fatal

I have sketched an extreme case, but whatever causes grave vertigo

Vertigo as a result of chronic dyspepsia in any of its forms is rare,

In a third form the gastro-intestinal tract is but indirectly concerned.

This is due simply to the influence exerted on an over-sensitive head

Aural Vertigo.—Vertigo may be due to a variety of irritative causes

Vertigo from Causes acting on the External Ear.—In animals I have

Thus, injections of cool water in some cases (or in others of water at

The tendency of aurists is, I believe, to explain the phenomena by

Middle-ear vertigo may arise from any inflammation of the part or

Inner-ear vertigo seems to be due to irritations, auditory, mechanical,

The acute attack is nearly always preceded by more or less

The attack in the gravest forms is often abrupt, and, according to

There should be no trouble in distinguishing the cases in which

Vertigo from coarse organic lesion of brain, such as a tumor, is

Growths or other causes of irritation in the crura of the cerebrum or

OCULAR CAUSES OF VERTIGO.—For the most part, the eyes as a

A number of eye conditions cause giddiness or increase it or

Abrupt change in intraocular pressure is another cause, as in acute

Permanent vertigo of quite severe character may arise from

Objectives2 Polymorphisms in Drug-Transporter Genes 21

CYP2D62A/2×2 Fatality in a breast-fed baby whose mother is a UM [26]

Hydrocodone CYP2D62A/41 Fatality in a child who also received concurrent [33]